Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors

ABSTRACT

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren&#39;s syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds and to the use of the compounds in therapy. More particularly,it relates to pyrazolyl urea, thiourea, guanidine and cyanoguanidinecompounds which exhibit TrkA kinase inhibition, and which are useful inthe treatment of pain, cancer, inflammation/inflammatory diseases,neurodegenerative diseases, certain infectious diseases, Sjogren'ssyndrome, endometriosis, diabetic peripheral neuropathy, prostatitis orpelvic pain syndrome.

The current treatment regimens for pain conditions utilize severalclasses of compounds. The opioids (such as morphine) have severaldrawbacks including emetic, constipatory and negative respiratoryeffects, as well as the potential for addictions. Non-steroidalanti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) alsohave drawbacks including insufficient efficacy in treating severe pain.In addition, COX-1 inhibitors can cause ulcers of the mucosa.Accordingly, there is a continuing need for new and more effectivetreatments for the relief of pain, especially chronic pain.

Trk's are the high affinity receptor tyrosine kinases activated by agroup of soluble growth factors called neurotrophins (NT). The Trkreceptor family has three members: TrkA, TrkB and TrkC. Among theneurotrophins are (i) nerve growth factor (NGF) which activates TrkA,(ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activateTrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed inneuronal tissue and are implicated in the maintenance, signaling andsurvival of neuronal cells (Patapoutian, A. et al., Current Opinion inNeurobiology, 2001, 11, 272-280).

Inhibitors of the Trk/neurotrophin pathway have been demonstrated to beeffective in numerous pre-clinical animal models of pain. For example,antagonistic NGF and TrkA antibodies such as RN-624 have been shown tobe efficacious in inflammatory and neuropathic pain animal models(Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn, P. K. et al.(2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995) Nat. Med. 1,774-780; Ma, Q. P. and Woolf, C. J. (1997) NeuroReport 8, 807-810;Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003)Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15,355-361; Jaggar, S. I. et al. (1999) Br. J Anaesth. 83, 442-448) andneuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999)Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Herzberg, U. etal., Pain 79, 265-274 (1997) Neuroreport 8, 1613-1618; Theodosiou, M. etal. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci.23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117-120).

It has also been shown that NGF secreted by tumor cells and tumorinvading macrophages directly stimulates TrkA located on peripheral painfibers. Using various tumor models in both mice and rats, it wasdemonstrated that neutralizing NGF with a monoclonal antibody inhibitscancer related pain to a degree similar or superior to the highesttolerated dose of morphine. Because TrkA kinase may serve as a mediatorof NGF driven biological responses, inhibitors of TrkA and/or other Trkkinases may provide an effective treatment for chronic pain states.

Recent literature has also shown that overexpression, activation,amplification and/or mutation of Trk kinases are associated with manycancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003,3, 203-216), ovarian (Davidson. B., et al., Clin. Cancer Res. 2003, 9,2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949),melanoma (Truzzi, F., et al., Dermato-Endocrinology 2008, 3 (1), pp.32-36), head and neck cancer (Yilmaz, T., et al., Cancer Biology andTherapy 2010, 10 (6), pp. 644-653), gastric carcinoma (Du, J. et al.,World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), lungcarcinoma (Ricci A., et al., American Journal of Respiratory Cell andMolecular Biology 25 (4), pp. 439-446), breast cancer (Jin, W., et al.,Carcinogenesis 2010, 31 (11), pp. 1939-1947), Glioblastoma (Wadhwa, S.,et al., Journal of Biosciences 2003, 28 (2), pp. 181-188),medulloblastoma (Gruber-Olipitz, M., et al., Journal of ProteomeResearch 2008, 7 (5), pp. 1932-1944), secratory breast cancer (Euthus,D. M., et al., Cancer Cell 2002, 2 (5), pp. 347-348), salivary glandcancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention andTreatment 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma(Greco, A., et al., Molecular and Cellular Endocrinology 2010, 321 (1),pp. 44-49) and adult myeloid leukemia (Eguchi, M., et al., Blood 1999,93 (4), pp. 1355-1363). In preclinical models of cancer, non-selectivesmall molecule inhibitors of TrkA, B and C were efficacious in bothinhibiting tumor growth and stopping tumor metastasis (Nakagawara, A.(2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia,1-10; Pierottia, M. A. and Greco A., (2006) Cancer Letters 232:90-98;Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351).

In addition, inhibition of the neurotrophin/Trk pathway has been shownto be effective in treatment of pre-clinical models of inflammatorydiseases with NGF antibodies or non-selective small molecule inhibitorsof TrkA. For example, inhibition of the neurotrophin/Trk pathway hasbeen implicated in preclinical models of inflammatory lung diseasesincluding asthma (Freund-Michel, V; Frossard, N., Pharmacology &Therapeutics (2008) 117(1), 52-76), interstitial cystitis (Hu Vivian Y;et. al. The Journal of Urology (2005), 173(3), 1016-21), bladder painsyndrome (Liu, H.-T., et al., (2010) BJU International, 106 (11), pp.1681-1685), inflammatory bowel diseases including ulcerative colitis andCrohn's disease (Di Mola, F. F, et. al., Gut (2000) 46(5), 670-678) andinflammatory skin diseases such as atopic dermatitis (Dou, Y.-C., et.al. Archives of Dermatological Research (2006) 298(1), 31-37), eczemaand psoriasis (Raychaudhuri, S. P., et al., J. Investigative Dermatology(2004) 122(3), 812-819).

The TrkA receptor is also thought to be critical to the disease processin the infection of the parasitic infection of Trypanosoma cruzi (Chagasdisease) in human hosts (de Melo-Jorge, M. et al., Cell Host & Microbe(2007) 1(4), 251-261).

Trk inhibitors may also find use in treating disease related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases. Bone metastases are afrequent complication of cancer, occurring in up to 70 percent ofpatients with advanced breast or prostate cancer and in approximately 15to 30 percent of patients with carcinoma of the lung, colon, stomach,bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases cancause severe pain, pathologic fractures, life-threatening hypercalcemia,spinal cord compression, and other nerve-compression syndromes. Forthese reasons, bone metastasis is a serious and costly complication ofcancer. Therefore, agents that can induce apoptosis of proliferatingosteoblasts would be highly advantageous. Expression of TrkA receptorshas been observed in the bone-forming area in mouse models of bonefracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). In addition,localization of NGF was observed in almost all bone-forming cells (K.Asaumi, et al.). Recently, it was demonstrated that a Trk inhibitorinhibits the tyrosine signaling activated by neurotrophins binding toall three of the Trk receptors in human hFOB osteoblasts (J. Pinski, etal., (2002) 62, 986-989). These data support the rationale for the useof Trk inhibitors for the treatment of bone remodeling diseases, such asbone metastases in cancer patients.

Trk inhibitors may also find use in treating diseases and disorders suchas Sjogren's syndrome (Fauchais, A. L., et al., (2009) ScandinavianJournal of Rheumatology, 38(1), pp. 50-57), endometriosis (Barcena DeArellano, M. L., et al., (2011) Reproductive Sciences, 18(12), pp.1202-1210; Barcena De Arellano, et al., (2011) Fertility and Sterility,95(3), pp. 1123-1126; Cattaneo, A., (2010) Current Opinion in MolecularTherapeutics, 12(1), pp. 94-106), diabetic peripheral neuropathy (Kim,H. C., et al., (2009) Diabetic Medicine, 26 (12), pp. 1228-1234;Siniscalco, D., et al., (2011) Current Neuropharmacology, 9(4), pp.523-529; Ossipov, M. H., (2011) Current Pain and Headache Reports,15(3), pp. 185-192), and prostatitis and pelvic pain syndrome (Watanabe,T., et al., (2011) BJU International, 108(2), pp. 248-251; and Miller,L. J., et al., (2002) Urology, 59(4), pp. 603-608).

Several classes of small molecule inhibitors of Trk kinases said to beuseful for treating pain or cancer are known (Expert Opin. Ther. Patents(2009) 19(3), 305-319).

SUMMARY OF THE INVENTION

It has now been found that pyrrolidinyl urea, thiourea, guanidine andcyanoguanidine compounds are inhibitors of TrkA, and useful for treatingdisorders and diseases such as pain, including chronic and acute pain.Compounds of the invention useful in the treatment of multiple types ofpain including inflammatory pain, neuropathic pain, and pain associatedwith cancer, surgery, or bone fracture. In addition, compounds of theinvention are useful for treating cancer, inflammation or inflammatorydiseases, neurodegenerative diseases, certain infectious diseases,Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy,prostatitis or pelvic pain syndrome, and diseases related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

More specifically, provided herein are compounds of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein Ring A, Ring C and X are asdefined herein.

Another aspect of the present invention provides methods of treating adisease or disorder modulated by TrkA, comprising administering to amammal in need of such treatment an effective amount of a compound ofthis invention or a stereoisomer, solvate or pharmaceutically acceptablesalt thereof. In one embodiment, the disease and disorders includechronic and acute pain, including but not limited to inflammatory pain,neuropathic pain, and pain associated with cancer, surgery, or bonefracture. In another embodiment, the disease and disorders include, butare not limited to, cancer, inflammation or inflammatory diseases,neurodegenerative diseases, certain infectious diseases, Sjogren'ssyndrome, endometriosis, diabetic peripheral neuropathy, prostatitis orpelvic pain syndrome, and diseases related to an imbalance of theregulation of bone remodeling, such as osteoporosis, rheumatoidarthritis, and bone metastases. In one embodiment, the treatmentincludes treating the mammal with a compound of this invention incombination with an additional therapeutic agent.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention or apharmaceutically acceptable salt thereof.

Another aspect of the present invention provides the compounds of thepresent invention for use in therapy.

Another aspect of the present invention provides the compounds of thepresent invention for use in the treatment of disease and disorders suchas chronic and acute pain, including but not limited to inflammatorypain, neuropathic pain, and pain associated with cancer, surgery, orbone fracture. Another aspect of the present invention provides thecompounds of the present invention for use in the treatment of diseaseand disorders selected from cancer, inflammation or inflammatorydiseases, neurodegenerative diseases, certain infectious diseases,Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy,prostatitis or pelvic pain syndrome, and diseases related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof disease and disorders such as chronic and acute pain including, butnot limited to, inflammatory pain, neuropathic pain, and pain associatedwith cancer, surgery, or bone fracture.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof disease and disorders selected from cancer, inflammation orinflammatory diseases, neurodegenerative diseases, certain infectiousdiseases, Sjogren's syndrome, endometriosis, diabetic peripheralneuropathy, prostatitis or pelvic pain syndrome, and diseases related toan imbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

Another aspect of the present invention provides intermediates forpreparing compounds of Formula I.

Another aspect of the present invention includes methods of preparing,methods of separation, and methods of purification of the compounds ofthis invention.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds, and pharmaceutical formulations thereof,that are useful in the treatment of diseases, conditions and/ordisorders modulated by TrkA.

A representative compound of the invention (See Table B below), wasfound to be highly selective for TrkA over a panel of about 230 otherkinases at 10 μM concentration. In addition, compounds of the inventionsuch as those shown in Table A below, were found to be at least 1000fold more selective for TrkA versus p38a.

One embodiment provides a compound of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

X is O, S, NH or N—CN;

Ring A is

R¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-3C)alkyl;

R² is (1-3C)alkyl [optionally substituted with 1 to 5 fluoros] or(3-4C)cycloalkyl [optionally substituted with one or two fluoros];

R⁶ is H or CH₃;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl orhetAr²;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from (1-6C)alkyl andhalogen;

R⁴ is hetAr⁴, hetAr⁵ or hydroxy(1-6C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and substituted with one or moresubstituents independently selected from (1-6C)alkyl [optionallysubstituted with 1-5 fluoros], halogen, CN, hydroxy(1-6C)alkyl,(3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂—, (3-6C cycloalkyl)C(═O)—, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6Calkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoro)alkoxy, fluoro(1-6Calkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and(3-4C cycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more substituents independently selectedfrom F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen.

One embodiment of Formula I includes compounds of Formula I-I

wherein:

X is O, S, NH or N—CN;

Ring A is

R¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-3C)alkyl;

R² is (1-3C)alkyl [optionally substituted with 1 to 5 fluoros] or(3-4C)cycloalkyl [optionally substituted with one or two fluoros];

R⁶ is H or CH₃;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl orhetAr²;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and 0;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from (1-6C)alkyl andhalogen;

R⁴ is hetAr⁴ or hetAr⁵;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and substituted with one or moresubstituents independently selected from (1-6C)alkyl [optionallysubstituted with 1-5 fluoros], halogen, CN, hydroxy(1-6C)alkyl,(3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂—, (3-6C cycloalkyl)C(═O)—, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6Calkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoro)alkoxy, fluoro(1-6Calkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and(3-4C cycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more substituents independently selectedfrom F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical “alkoxyalkyl” is attached to the structure inquestion by the alkyl group.

The terms “(1-6C)alkyl” and “(1-3C)alkyl” as used herein refer tosaturated linear monovalent hydrocarbon radicals of one to six carbonatoms, and one to three carbon atoms, respectively, or a branchedsaturated monovalent hydrocarbon radical of three to six carbon atoms,three to four carbon atoms, or three carbon atoms, respectively.Examples include, but are not limited to, methyl, ethyl, 1-propyl,2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl,2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and3,3-dimethyl-2-butyl.

“(1-6C alkyl)amino” refers to a R—NH— radical where R is (1-6C)alkyl asdefined above.

“Di(1-6C alkyl)amino” refers to a R₂—N— radical where each R is(1-6C)alkyl as defined above.

“Difluoro(1-6C alkyl)amino” refers to a R—NH— radical where R is(1-6C)alkyl as defined above, wherein the alkyl portion is substitutedwith two fluoros.

“Trifluoro(1-6C alkyl)amino” refers to a R—NH— radical where R is(1-6C)alkyl as defined above, wherein the alkyl portion is substitutedwith two fluoros.

“(1-6C)alkoxy” refers to an RO— radical where R is (1-6C)alkyl asdefined above. Examples include methoxy, ethoxy, and the like.

“(1-6C)acyl” means a RC(═O)— radical where R is a linear saturatedmonovalent hydrocarbon radical of one to five carbon atoms or a branchedsaturated monovalent hydrocarbon radical of three to five carbon atoms,e.g., methylcarbonyl, and the like.

“(1-3C Alkoxy)(1-6C)alkyl” and “(1-3C alkoxy)(1-4C)alkyl” mean a linearsaturated monovalent hydrocarbon radical of one to six carbon atoms orone to four carbon atoms, or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms or three to four carbon atoms,respectively, wherein one of the carbon atoms is substituted with one(1-3C)alkoxy group as defined herein.

“Amino” means a —NRR′ group where R and R′ are independently selectedfrom hydrogen or (1-3C)alkyl as defined herein. Examples include H₂N—,CH₃NH—, (CH₃)₂N, and the like.

“Aminocarbonyl” means a RR′NCO— radical where R and R′ are independentlyhydrogen or (1-6C)alkyl as defined herein. Examples include H₂NCO—,dimethylaminocarbonyl, and the like.

“(1-6C)Alkylsulfonyl” means a —SO₂R radical where R is (1-6C)alkyl asdefined above, e.g., methylsulfonyl, and the like.

“Halogen” as used herein means F, Cl, Br or I.

“Heterocycle” refers to a saturated or partially unsaturated ring systemhaving one or more ring heteroatoms as recited for the specificheterocyclic group, wherein the heterocycle is optionally substitutedwith substituents as defined for that particular heterocyclic group.

“Heteroaryl” refers to a 5-6 membered unsaturated ring system having oneor more ring heteroatoms as recited for the specific heteroaryl group,wherein the heteroaryl is optionally substituted with substituents asdefined for that particular heteroaryl group.

“Hydroxy(1-6C)alkyl” means a linear saturated hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms or three to four carbon atoms,respectively, wherein one of the carbon atoms is substituted with ahydroxy (OH) group.

“Hydroxy(1-6C)alkoxy” means a (1-6C)alkoxy group as defined above,wherein one of the carbon atoms is substituted with a hydroxyl (OH)group.

“Monofluoro(1-6C)alkyl”, “difluoro(1-6C)alkyl” and“trifluoro(1-6C)alkyl” refer to a (1-6C)alkyl group as defined hereinwherein one to three hydrogen atoms, respectively, is replaced by afluoro group.

“Tetrafluoro(2-6C)alkyl” and “pentafluoro(2-6C)alkyl” refer to a linearsaturated monovalent hydrocarbon radical of two to six carbon atoms or abranched saturated monovalent hydrocarbon radical of three to six carbonatoms wherein four to five hydrogen atoms, respectively, is replaced bya fluoro group.

“Trifluoro(1-3C alkyl)amido” means a (1-3C alkyl)C(═O)NH— group whereinone of the carbons is substituted with three fluoros.

“Trifluoro(1-6C)alkoxy” means a (1-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with three fluoros.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as heteroatom substitutedheteroaryl or heterocyclic groups and the like, which are illustrated inthe following general and specific examples:

where G′=O, S, or NR, and though one form is named, described, displayedand/or claimed herein, all the tautomeric forms are intended to beinherently included in such name, description, display and/or claim.

In one embodiment of Formula I, X is O.

In one embodiment, X is S.

In one embodiment, X is NH.

In one embodiment, X is N—CN.

In one embodiment of Formula I, R¹ is phenyl optionally substituted withone or more substituents independently selected from halogen or(1-3C)alkyl.

In one embodiment of Formula I, R¹ is phenyl.

In one embodiment of Formula I, R² is (1-3C)alkyl [optionallysubstituted with 1 to 5 fluoros] or (3-4C)cycloalkyl [optionallysubstituted with one or two fluoros].

In one embodiment of Formula I, R² is (1-3C)alkyl optionally substitutedwith 1 to 5 fluoros. In one embodiment, R² is methyl, isopropyl,trifluoromethyl or 2,2,2-trifluoroethyl.

In one embodiment of Formula I, R² is (3-4C)cycloalkyl optionallysubstituted with one or two fluoros. In one embodiment, R² iscyclopropyl or 2,2-difluorocyclopropyl.

In one embodiment of Formula I, R⁶ is H or CH₃. In one embodiment, R⁶ isH. In one embodiment, R⁶ is CH₃.

In one embodiment of Formula I, Ring C is formula C-1:

where R³, R⁴ and R⁵ are as defined for Formula I.

In one embodiment, R³ is (1-6C)alkyl. In one embodiment, R³ is methyl orethyl.

In one embodiment, R³ is hydroxy(1-6C)alkyl. An example of R³ is2-hydroxyethyl.

In one embodiment, R³ is Ar², where Ar² is phenyl optionally substitutedwith one or more substituents independently selected from halogen and(1-6C)alkyl.

In one embodiment, R³ when represented by Ar² is phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl or3-chloro-2-fluorophenyl. In one embodiment, R³ when represented by Ar²is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-methylphenyl, 3-methylphenyl or 4-methylphenyl. In one embodiment, R³is phenyl.

In one embodiment, R³ is hetCyc¹, where hetCyc¹ is a 5-6-memberedsaturated or partially unsaturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O. In one embodiment, R³is a pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, or morpholinyl ring. In one embodiment,R³ is tetrahydro-2H-pyran-4-yl.

In one embodiment, R³ is (3-7C)cycloalkyl. In one embodiment R³ iscyclohexyl.

In one embodiment, R³ is hetAr², where hetAr² is 5-6 membered heteroarylring having 1-3 ring heteroatoms independently selected from N, O and Sand optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl and halogen. In one embodiment, R³ is thienyl,furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl,pyrazinyl, or pyridazinyl optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen. In oneembodiment, R³ is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and halogen. In one embodiment, R³ is pyrazolyl, pyridyl orpyridazinyl optionally substituted with (1-6C)alkyl or halogen. In oneembodiment, R³ when represented by hetAr² is 1-methyl-1H-pyrazol-4-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyridazinyl or 3-chloropyrid-5-yl.

In one embodiment, R³ is selected from Ar² and hetAr².

In one embodiment, R³ is Ar². In one embodiment, R³ is phenyl.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O and substituted with one or more substituents independentlyselected from (1-6C)alkyl [optionally substituted with 1-5 fluoros],halogen, CN, hydroxy(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂—, (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoro)alkoxy, fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino.

In one embodiment, R⁴ is hetAr⁴ where hetAr⁴ is pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or1,2,4-oxadiazolyl substituted with one or more substituentsindependently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂-(3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino,trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino.

In one embodiment, R⁴ is hetAr⁴ where hetAr⁴ is pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or1,2,4-oxadiazolyl substituted with one or more substituentsindependently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy)(1-3C)trifluoroalkyl and cyclopropylNH—.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or1,2,4-oxadiazolyl substituted with 1-3 substituents independentlyselected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl,cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN,H₂N—, (CH₃)₂N—, 2-hydroxyethyl, 2-methoxyethyl,1-(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl, cyclopropylcarbonyl,methylsulfonyl and cyclopropylNH—.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is pyridyl, pyrimidinyl orpyridazinyl substituted with 1-3 substituents independently selectedfrom fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl,trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H₂N—,CH₃NH—, (CH₃)₂N—, and cyclopropylNH—.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is pyrazolyl substitutedwith 1-3 substituents independently selected from fluoro, methyl, ethyl,isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl,2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H₂N—, (CH₃)₂N—,2-hydroxyethyl, 2-methoxyethyl,1-(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl, cyclopropylcarbonyl,methylsulfonyl and cyclopropylNH—.

In one embodiment, R⁴ when represented by hetAr⁴ is selected from thestructures:

In one embodiment, R⁴ is hetAr⁵, where hetAr⁵ is a group selected fromthe structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more substituents independently selectedfrom F and (1-3C)alkyl optionally substituted with 1-3 fluoros.

In one embodiment, R⁴ when represented by hetAr⁵ is selected from thestructures:

In one embodiment, R⁴ is hydroxy(1-6C)alkoxy. In one embodiment, R⁴ is2-hydroxyethoxy.

In one embodiment, R⁵ is (1-6C)alkyl. In one embodiment, R⁵ is methyl,ethyl, propyl, isopropyl or butyl.

In one embodiment, R⁵ is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl.In one embodiment, R⁵ is fluoromethyl, 2-fluoroethyl, difluoromethyl,2,2-difluoroethyl, 1,3-difluoroprop-2-yl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1,1,2,2-tetrafluoropropaneor 2,2,3,3,3-pentafluoropropyl.

In one embodiment, R⁵ is halogen. In one embodiment, R⁵ is F. In oneembodiment, R⁵ is Cl. In one embodiment, R⁵ is Br.

In one embodiment, R⁵ is CN.

In one embodiment, R⁵ is (1-4C)alkoxy. In one embodiment, R⁵ is methoxyor ethoxy.

In one embodiment, R⁵ is hydroxy(1-4C)alkyl. In one embodiment, R⁵ ishydroxymethyl or 3-hydroxypropyl.

In one embodiment, R⁵ is (1-4C alkyl)OC(═O)—. In one embodiment, R⁵ isCH₃CH₂OC(═O)—.

In one embodiment, R⁵ is (1-6C)alkylthio. In one embodiment, R⁵ ismethylthio (MeS—).

In one embodiment, R⁵ is phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy. In one embodiment, R⁵ is phenyl optionally substitutedwith one or more substituents independently selected from F, Cl, methyl,ethyl, methoxy and ethoxy. In one embodiment, R⁵ is phenyl.

In one embodiment, R⁵ is (3-4C)cycloalkyl. In one embodiment, R⁵ iscyclopropyl. In one embodiment, R⁵ is cyclobutyl.

In one embodiment, R⁵ is amino. In one embodiment, R⁵ is NH₂.

In one embodiment, R⁵ is aminocarbonyl. In one embodiment, R⁵ isH₂NC(═O)—.

In one embodiment, R⁵ is trifluoro(1-3C alkyl)amido. In one embodiment,R⁵ is CF₃C(═O)NH—.

In one embodiment, R⁵ is halogen, CN, (1-6C)alkyl, (1-4C)alkoxy,hydroxy(1-4C)alkyl, or phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy.

In one embodiment, R⁵ is selected from halogen, and (1-6C)alkyl.

In one embodiment, R⁵ is selected from methyl, Cl and Br.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, or R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated heterocyclic ring having a ringheteroatom selected from N, O or S, wherein said ring nitrogen atom isoptionally substituted with (1-6C alkyl)C(═O)O— or (1-6C)acyl, and saidsulfur ring atom is optionally oxidized to S(═O) or SO₂.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl. In one embodiment, Ring C when R⁴ and R⁵ together with theatoms to which they are attached form a 5-6 membered saturatedcarbocyclic ring is selected from the structures:

where R³ is as defined for Formula I.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said ring N atom is optionally substituted with (1-6Calkyl)C(═O)O—, (1-6C alkyl)C(═O)—, (1-6C)alkyl or oxo, and said S ringatom is optionally oxidized to S(═O) or SO₂. In one embodiment, Ring Cwhen R⁴ and R⁵ together with the atoms to which they are attached form a5-6 membered saturated heterocyclic ring is selected from thestructures:

where R³ is as defined for Formula I.

In one embodiment, Ring C is formula C-2

where R^(3a), R^(4a) and R^(5a) are as defined for Formula I.

In one embodiment, R^(3a) is hydrogen.

In one embodiment, R^(3a) is halogen.

In one embodiment, R^(3a) is (1-6C)alkyl. In one embodiment, R^(3a) ismethyl.

In one embodiment, R^(3a) is trifluoro(1-6C)alkyl. In one embodiment,R^(3a) is CF₃.

In one embodiment, R^(3a) is (3-6C)cycloalkyl. In one embodiment, R^(3a)is cyclopropyl.

In one embodiment, R^(3a) is phenyl optionally substituted with one ormore substituents independently selected from halogen and (1-6C)alkyl.In one embodiment, R^(3a) is phenyl, fluorophenyl or methylphenyl, forexample include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl or 3-chloro-2-fluorophenyl. In one embedment,R^(3a) is phenyl.

In one embodiment, R^(3a) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, O and S and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3a) is a thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, orpyridazinyl ring optionally substituted with (1-6C)alkyl or halogen. Inone embodiment, R^(3a) is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3a) is pyrazolyl, pyridylor pyridazinyl optionally substituted with (1-6C)alkyl or halogen.

In one embodiment, R^(4a) is hydrogen.

In one embodiment, R^(4a) is (1-6C)alkyl. In one embodiment, R^(4a) ismethyl, ethyl or isopropyl.

In one embodiment, R^(4a) is trifluoro(1-6C)alkyl. In one embodiment,R^(4a) is 2,2,2-trifluoroethyl.

In one embodiment, R^(4a) is phenyl optionally substituted with one ormore substituents independently selected from (1-6C)alkyl, halogen, CN,CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl,(1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and(1-3C alkoxy)(1-3C alkyl)OC(═O)—. In one embodiment, R^(4a) is phenyloptionally substituted with one or more substituents independentlyselected from methyl, F, Cl, CN, methoxy, CH₃OC(═O)—, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, methylthio, CH₃SO₂—,HOC(═O)— or CH₃OCH₂CH₂OC(═O)—. In certain embodiments, R^(4a) is phenyloptionally substituted with one or two of said substituents. In oneembodiment, R^(4a) is phenyl.

In one embodiment, R^(4a) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, S and O and optionallysubstituted with 1-2 substituents independently selected from(1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,(3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl. In oneembodiment, R^(4a) is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl,imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl,oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl orimidazo[1,2-a]pyridinyl optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, and(1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl. In one embodiment, R^(4a) ispyrazinyl.

In one embodiment, R^(5a) is as defined for Formula I.

In one embodiment, R^(5a) is selected from hydrogen, halogen,(1-6C)alkyl and phenyl.

In one embodiment, R^(5a) is hydrogen.

In one embodiment, R^(5a) is halogen.

In one embodiment, R^(5a) is (1-6C)alkyl. In one embodiment, R^(5a) ismethyl.

In one embodiment, R^(5a) is phenyl.

In one embodiment, Ring C is formula C-2, in which R^(3a) is(1-6C)alkyl, trifluoro(1-6C)alkyl or phenyl; R^(4a) is (1-6C)alkyl,trifluoro(1-6C)alkyl, phenyl or pyrazinyl; and R^(5a) is hydrogen,(1-6C)alkyl or phenyl.

In one embodiment, Formula I includes compounds of Formula I-a, wherein:

X is O; Ring C is C-1; R⁴ is hetAr⁴; and hetAr⁴, Ring A, R¹, R², R³, R⁴,R⁵ and R⁶ are as defined for Formula I.

In one embodiment, Formula I includes compounds of Formula I-b, wherein:

X is O; Ring C is C-1; R⁴ is hetAr⁵; and hetAr⁵, Ring A, R¹, R², R³, R⁴,R⁵ and R⁶ are as defined for Formula I.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated in a mixture of isomers such as a racemic mixture,or in an enantiomerically pure form.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention. Forexample, compounds of Formula I can exist in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which are useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I. Particular examples of saltsinclude hydrochloride salts or trifluoroacetate salts.

In one embodiment, the compounds of Formula I include the free base formof compounds of Examples 4, 5, 6, 11 and 12, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the compounds of Formula I include the hydrochloridesalts of compounds of Examples 4, 5, 6, 11 and 12.

In one embodiment, the compounds of Formula I include thetrifluoroacetate salts of compounds of Examples 4, 5, 6, 11 and 12.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The present invention also provides a process for the preparation of acompound of Formula I or a salt thereof as defined herein, whichcomprises:

(a) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula III

in the presence carbonyldiimidazole or triphosgene and a base; or

(b) for a compound of Formula I where X is S, coupling a correspondingcompound having the formula H

with a corresponding compound of formula III

in the presence di(1H-imidazol-2-yl)methanethione and a base; or

(c) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula IV

where L¹ is a leaving group, in the presence of a base; or

(d) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula V

where L² is a leaving group, with a corresponding compound having theformula III

in the presence of a base; or

(e) for a compound of Formula I where X is O, activating a correspondingcompound having the formula VI

with diphenylphosphoryl azide followed by coupling the activatedintermediate with a corresponding compound having the formula III

in the presence a base; or

(f) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula VII

in the presence of a base; or

(g) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula VIII

with a corresponding compound having the formula III

in the presence of a base; and

optionally removing protecting groups and optionally preparing apharmaceutically acceptable salt thereof.

In the above methods, the term “corresponding” means that thedefinitions for the “corresponding compound” are as defined for FormulaI unless stated otherwise.

Referring to method (a), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents includedichloromethane, dichloroethane, THF, DMA and DMF. The reaction isconveniently performed at ambient temperature.

Referring to method (b), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents includedichloromethane, dichloroethane, THF, DMA and DMF. The reaction isconveniently performed at ambient temperature.

Referring to method (c), the leaving group may be, for example, phenoxyor 4-nitrophenoxy. The base may be an amine base, such as triethylamineor diisopropylethylamine. Suitable solvents include DMA, DMF and DCE.The reaction is conveniently performed at ambient temperature orelevated temperatures.

Referring to method (d), the leaving group may be, for example, phenoxyor 4-nitrophenoxy. The base may be an amine base, such as triethylamineor diisopropylethylamine. Suitable solvents include DCE, DMA and DMF.The reaction is conveniently performed at ambient temperature.

Referring to method (e), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents includetoluene and DMF. The reaction is conveniently performed at elevatedtemperatures, for example the reflux temperature of the solvent.

Referring to methods (f) and (g), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents include DCM,DCE, DMF and THF. The reaction is conveniently performed at temperaturesbetween about 0° C. and ambient temperature.

Amine groups in compounds described in any of the above methods may beprotected with any convenient amine protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2″^(d) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof amine protecting groups include acyl and alkoxycarbonyl groups, suchas t-butoxycarbonyl (BOC) and [2-(trimethylsilyl)ethoxy]methyl (SEM).Likewise, carboxyl groups may be protected with any convenient carboxylprotecting group, for example as described in Greene & Wuts, eds.,“Protecting Groups in Organic Synthesis”, 2^(nd) ed. New York; JohnWiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include(1-6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groupsmay be protected with any convenient alcohol protecting group, forexample as described in Greene & Wuts, eds., “Protecting Groups inOrganic Synthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991.Examples of alcohol protecting groups include benzyl, trityl, silylethers, and the like.

Amine groups in compounds described in any of the above methods may beprotected with any convenient amine protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof amine protecting groups include acyl and alkoxycarbonyl groups, suchas t-butoxycarbonyl (BOC), phenoxycarbonyl, and[2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groups may beprotected with any convenient carboxyl protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof carboxyl protecting groups include (1-6C)alkyl groups, such asmethyl, ethyl and t-butyl. Alcohol groups may be protected with anyconvenient alcohol protecting group, for example as described in Greene& Wuts, eds., “Protecting Groups in Organic Synthesis”, 2^(nd) ed. NewYork; John Wiley & Sons, Inc., 1991. Examples of alcohol protectinggroups include benzyl, trityl, silyl ethers, and the like.

The compounds of the formulas II, V, VI, VII, and VIII are also providedas further aspects of the invention. In one embodiment, compounds of theformulas II, V, VI, VII, and VIII are useful as intermediates for thepreparation of compounds of Formula I.

Compounds of Formula I are useful in the treatment of pain, cancer,inflammation/inflammatory diseases, neurodegenerative diseases, certaininfectious diseases, Sjogren's syndrome, endometriosis, diabeticperipheral neuropathy, prostatitis or pelvic pain syndrome.

In one embodiment, compounds of Formula I are useful for treating pain,including chronic and acute pain. For example, compounds of Formula Iare useful in the treatment of multiple types of pain includinginflammatory pain, neuropathic pain, and pain associated with cancer,surgery or bone fracture.

In one embodiment, compounds of Formula I are useful for treating acutepain. Acute pain, as defined by the International Association for theStudy of Pain, results from disease, inflammation, or injury to tissues.This type of pain generally comes on suddenly, for example, after traumaor surgery, and may be accompanied by anxiety or stress, and is confinedto a given period of time and severity. In some instances, it can becomechronic.

In one embodiment, compounds of Formula I are useful for treatingchronic pain. Chronic pain, as defined by the International Associationfor the Study of Pain, is widely believed to represent a disease initself. It can be made much worse by environmental and psychologicalfactors. Chronic pain persists over a longer period than acute pain andis resistant to most medical treatments, generally over 3 months ormore. It can and often does cause severe problems for patients.

Compounds of Formula I are also useful for treating cancer. Particularexamples include neuroblastoma, ovarian, pancreatic, colorectal andprostate cancer.

Compounds of Formula I are also useful for treating inflammation andcertain infectious diseases. For example, compounds of Formula I may beused to treat interstitial cystitis (IC), painful bladder syndrome(PBS), urinary incontinence, asthma, atopic dermatitis, and psoriasis.

Compounds of Formula I are also useful for treating a neurodegenerativedisease in a mammal, comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt thereof inan amount effective to treat said neurodegenerative disease. In oneembodiment, compounds of Formula I may also be used to treatdemyelination and dysmyelination by promoting myelination, neuronalsurvival, and oligodendrocyte differentiation via blocking Sp35-TrkAinteraction. In one embodiment, the neurodegenerative disease ismultiple sclerosis. In one embodiment, the neurodegenerative disease isParkinson's disease. In one embodiment, the neurodegenerative disease isAlzheimer's disease.

Compounds of Formula I are also useful for treating certain infectiousdiseases such as Trypanosoma cruzi infection in a mammal.

Compounds of Formula I are also useful for treating Sjogren's syndromein a mammal.

Compounds of Formula I are also useful for treating endometriosis in amammal.

Compounds of Formula I are also useful for treating diabetic peripheralneuropathy in a mammal.

Compounds of Formula I are also useful for treating prostatitis in amammal.

Compounds of Formula I are also useful for treating pelvic pain syndromein a mammal.

Compounds of Formula I are also useful in treating diseases related toan imbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative measures. Beneficial or desired clinical results include, butare not limited to, alleviation, in whole or in part, of symptomsassociated with a disorder or condition, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

In certain embodiments, compounds of Formula I are useful for preventingdiseases and disorders as defined herein. The term “preventing” as usedherein means the prevention of the onset, recurrence or spread, in wholeor in part, of the disease or condition as described herein, or asymptom thereof, and includes to the administration of a compound ofFormula I prior to the onset of symptoms.

Accordingly, one embodiment of this invention provides a method oftreating pain in a mammal, comprising administering to said mammal inneed thereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat said pain. Inone embodiment, the pain is chronic pain. In one embodiment, the pain isacute pain. In one embodiment, the pain is inflammatory pain,neuropathic pain, or pain associated with cancer, surgery, or bonefracture.

Another embodiment of this invention provides a method of preventingpain in a mammal, comprising administering to said mammal in needthereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to prevent said pain. Inone embodiment, the pain is chronic pain. In one embodiment, the pain isacute pain. In one embodiment, the pain is inflammatory pain,neuropathic pain, or pain associated with cancer, surgery, or bonefracture.

Another embodiment of this invention provides a method of treatingcancer in a mammal, comprising administering to said mammal in needthereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat said cancer.

In one embodiment, provided herein is a method for treating a patientdiagnosed with a cancer having a dysregulation of TrkA, comprisingadministering to the patient a therapeutically effective amount of acompound of the invention or a pharmaceutically acceptable salt thereof.

In one embodiment, the dysregulation of TrkA comprises overexpression ofwild-type TrkA (autocrine activation).

In one embodiment, the dysregulation of TrkA comprises one or morechromosome translocations or inversions resulting in TrkA gene fusions.In one embodiment, the dysregulation is a result of genetictranslocations in which the expressed protein is a fusion proteincontaining residues from non-TrkA and TrkA proteins, and at a minimumthe TrkA kinase domain. In one embodiment, the TrkA fusion protein isLMNA-TrkA, TFG-TrkA, TPM3-TrkA, CD74-TrkA, NFASC-TrkA, MPRIP-TrkA,BCAN-TrkA, or TPR-TrkA, where:

LMNA=Prelamin-A/C;

TFG=TRK-fused gene protein;

TPM3=Tropomysin alpha-3;

CD74=HLA class II histocompatibility antigen gamma chain;

NFASC=Neurofascin;

MPRIP=MPRIP protein;

BCAN=Brevican core protein; and

TPR=Nucleoprotein TPR

In one embodiment, the dysregulation of TrkA comprises one or moredeletions, insertions or mutations in the TrkA protein. In oneembodiment, the dysregulation comprises a deletion of one or moreresidues from the TrkA protein, resulting in constitutive activity ofTrkA kinase. In one embodiment the deletion includes deletion ofresidues 303-377 in TrkA Isoform 2.

In one embodiment, the dysregulation of TrkA comprises a splicevariation in which the expressed protein is an alternatively splicedvariant of TrkA having one or more residues deleted resulting inconstitutive activity of TrkA kinase. In one embodiment, analternatively spliced form of TrkA with constitutive activity hasdeletions of exons 8, 9, and 11 resulting in an expressed proteinmissing residues 192-284 and 393-398 relative to TrkA Isoform 2.

Cancers identified as having dysregulation of TrkA (see literaturereferences below; also see www.cancer.gov and www.nccn.org) include:

(A) Cancers wherein the dysregulation of TrkA comprises one or morechromosome translocations or inversions resulting in TrkA gene fusions,including:

Cancer Literature reference(s) Standard of Care Non-Small Cell Vaishnaviet al. 2013: radiotherapy (e.g. radioiodide therapy, Lung Cancer NatureMedicine 19, external-beam radiation, radium 223 1469-1472 therapy),chemotherapeutics as single agents (e.g. afatinib dimaleate,bevacizumab, carboplatin, cetuximab, cisplatin, crizotinib, erlotinib,gefitinib, gemcitabine, methotrexate, paclitaxel, pemetrexed) orcombinations (e.g. carboplatin-paclitaxel, gemcitabine- paclitaxel,chemoradiation) Papillary Thyroid Caria et al. 2010: CancerRadiotherapies (e.g. radioiodide therapy, Carcinoma Genetics andexternal-beam radiation) and Cytogenetics 203: 21-29 chemotherapeutics(e.g. sorafenib, sunitinib, pazopanib) Glioblastoma Frattini et al.2013: Chemotherapeutics (e.g. bevacizumab, Multiforme Nature Genet.everolimus, lomustine, temozolomide) 45(10): 1141-9 ColorectalMartin-Zanca et al. Chemotherapeutics as single agents Carcinoma 1986:Nature 319: 743 (aflibercept, bevacizumab, capecitabine, cetuximab,fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab,regorafenib) or combinations (e.g. folfox, folfiri, capox,folfiri-bevacizumab, folfiri- cetuximab, xelox) Melanoma WO 2013/059740A1 Chemotherapeutics (e.g. aldesleukin, dabrafenib, dacarbazine,interferon alfa- 2b, ipilimumab, peginterferon alfa-2b, trametinib,vemurafenib)

(B) Cancers wherein the dysregulation of TrkA comprises one or moredeletions, insertions or mutations in the TrkA protein, including:

Cancer Literature reference(s) Standard of care Acute Myeloid Meyer2007: Leukemia 21: Chemotherapeutics as single leukemia 2171-2180 agents(e.g. arsenic trioxide, Reuther et al. 2000: Mol Cell cyclophosphamide,cytarabine, Biol 20: 8655-8666 daunorubicin, doxorubicin, vincristine)or combinations (e.g. ADE) Large Cell Marchetti et al 2008: HumanRadiotherapy (e.g. radioiodide Neuroendocrine Mutation 29(5): 609-616therapy, external-beam radiation, Carcinoma radium 223 therapy) and/orchemotherapeutics (e.g. cisplatin, carboplatin, etoposide) NeuroblastomaTacconelli et al 2004: Cancer Chemotherapeutics (e.g. Cell 6: 347cyclophosphamide, doxorubicin, vincristine)

(C) Cancers driven by overexpression of wild-type TrkA (autocrineactivation), including:

Cancer Literature Reference(s) Standard of care Prostate Carcinoma Walchet al: Clinical & Radiotherapy (e.g. radium 223 Experimental Metastasis17: 307-314 therapy) or chemotherapeutics Papatsoris et al 2007: Expert(e.g. abiraterone, cabazitaxel, Opinion on Investigational Drugsdegarelix, denosumab, docetaxel, 16(3): 303-309 enzalutamide,leuprolide, prednisone, sipuleucel-T) Neuroblastoma Van Noesel et al2004: Gene 325: Chemotherapeutics (e.g. 1-15 cyclophosphamide,doxorubicin, vincristine) Pancreatic Zhang et al 2005: OncologyChemotherapeutics as single Carcinoma Reports 14: 161-171 agents (e.g.erlotinib, fluorouracil, gemcitabine, mitomycin C) or combinations (e.g.gemcitabine-oxaliplatin) Melanoma Truzzi et al 2008: Journal ofChemotherapeutics (e.g. Investigative Dermatology aldesleukin,dabrafenib, 128(8): 2031 dacarbazine, interferon alfa-2b, ipilimumab,peginterferon alfa- 2b, trametinib, vemurafenib) Head and NeckKolokythas et al 2010: Journal of Radiotherapy and/or Squamous Cell Oraland Maxillofacial Surgery chemotherapeutics (e.g. Carcinoma 68(6):1290-1295 bleomycin, cetuximab, cisplatin, docetaxel, fluorouracil,methotrexate) Gastric Carcinoma Ni et al 2012: Asian PacificChemotherapeutics (e.g. Journal of Cancer Prevention 13: docetaxel,doxorubucin, 1511 fluorouracil, mitomycin C, trastuzumab)

In one embodiment, provided herein is a method for treating a patientdiagnosed with a cancer having a dysregulation of TrkA, comprisingadministering to the patient a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable saltthereof, wherein the cancer is selected from non-small cell lung cancer,papillary thyroid carcinoma, glioblastoma multiforme, acute myeloidleukemia, colorectal carcinoma, large cell neuroendocrine carcinoma,prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head andneck squamous cell carcinoma and gastric carcinoma.

In one embodiment, the compounds of the present invention are useful fortreating cancer in combination with one or more additional therapeuticagents or therapies that work by the same or a different mechanism ofaction.

In one embodiment, the additional therapeutic agent(s) is selected fromreceptor tyrosine kinase-targeted therapeutic agents, includingcabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, andtrastuzumab.

In one embodiment, the additional therapeutic agent(s) is selected fromsignal transduction pathway inhibitors, including Ras-Raf-MEK-ERKpathway inhibitors (e.g. sorafenib, trametinib, vemurafenib),PI3K-Akt-mTOR-S6K pathway inhibitors (e.g. everolimus, rapamycin,perifosine, temsirolimus) and modulators of the apoptosis pathway (e.g.obataclax).

In one embodiment, the additional therapeutic agent(s) is selected fromcytotoxic chemotherapeutics, including arsenic trioxide, bleomycin,cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide,cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin,etoposide, fluorouracil, gemcitabine, irinotecan, lomustine,methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed,temozolomide, and vincristine.

In one embodiment, the additional therapeutic agent(s) is selected fromangiogenesis-targeted therapies, including aflibercept and bevacizumab.

In one embodiment, the additional therapeutic agent(s) is selected fromimmune-targeted agents, including aldesleukin, ipilimumab,lambrolizumab, nivolumab, sipuleucel-T.

In one embodiment, the additional therapeutic agent(s) is selected fromagents active against the TrkA pathway, including NGF-targetedbiopharmaceuticals such as NGF antibodies, and panTrk inhibitors.

In one embodiment, the additional therapeutic agent or therapy isradiotherapy, including radioiodide therapy, external-beam radiation andradium 223 therapy.

In one embodiment, the additional therapeutic agent(s) includes any oneof the above listed therapies or therapeutic agents which are standardsof care in cancers wherein the cancer has a dysregulation of TrkA.

In one embodiment, provided herein is a method of treating cancer in apatient, comprising administering to said patient a compound of theinvention or a pharmaceutically acceptable salt thereof, in combinationwith at least one additional therapy or therapeutic agent selected fromradiotherapy (e.g. radioiodide therapy, external-beam radiation, radium223 therapy), cytotoxic chemotherapeutics (e.g. arsenic trioxide,bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin,cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel,doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan,lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel,pemetrexed, temozolomide, vincristine), tyrosine kinasetargeted-therapeutics (e.g. afatinib, cabozantinib, cetuximab,crizotinib, dabrafenib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, pazopanib, panitumumab, pertuzumab, regorafenib, sunitinib,trastuzumab), apoptosis modulators and signal transduction inhibitors(e.g. everolimus, perifosine, rapamycin, sorafenib, temsirolimus,trametinib, vemurafenib), immune-targeted therapies (e.g. aldesleukin,interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone,sipuleucel-T) and angiogenesis-targeted therapies (e.g. aflibercept,bevacizumab), wherein the amount of the compound of the invention or apharmaceutically acceptable salt thereof is, in combination with theadditional therapy or therapeutic agent, is effective in treating saidcancer. These additional therapeutic agents may be administered with oneor more compounds of the invention as part of the same or separatedosage forms, via the same or different routes of administration, and onthe same or different administration schedules according to standardpharmaceutical practice known to one skilled in the art.

Also provided herein is (i) a pharmaceutical combination for treatingcancer in a patient in need thereof, which comprises (a) a compound ofthe invention or a pharmaceutically acceptable salt thereof, (b) anadditional therapeutic agent and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of a tumor disease, wherein the amountsof the compound or salt thereof and of the additional therapeutic agentare together effective in treating said cancer; (ii) a pharmaceuticalcomposition comprising such a combination; (iii) the use of such acombination for the preparation of a medicament for the treatment ofcancer; and (iv) a commercial package or product comprising such acombination as a combined preparation for simultaneous, separate orsequential use; and to a method of treatment of cancer a patient in needthereof.

In one embodiment, the combination therapy is for treating a cancer isselected from non-small cell lung cancer, papillary thyroid carcinoma,glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma,large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma,pancreatic carcinoma, melanoma, head and neck squamous cell carcinomaand gastric carcinoma.

Another embodiment of this invention provides a method of treatinginflammation or an inflammatory disease or disorder in a mammal,comprising administering to said mammal in need thereof one or morecompounds of Formula I or a pharmaceutically acceptable salt thereof inan amount effective to treat said inflammation. In one embodiment, theinflammatory disease is inflammatory lung diseases (such as asthma),interstitial cystitis, bladder pain syndrome, inflammatory boweldiseases (including ulcerative colitis and Crohn's disease), andinflammatory skin diseases such as atopic dermatitis.

In one embodiment, the method of treating inflammation or aninflammatory disease or disorder comprises administering a compound ofthe invention in combination with one or more additional agents.Examples of additional agents include anti-TNF treatments (for examplemonoclonal antibody such as infliximab (Remicade), adalimumab (Humira),certolizumab pegol (Cimzia), and golimumab (Simponi), or a circulatingreceptor fusion protein such as etanercept (Enbrel)), antimetabolite andantifolate drug (for example Methotrexate), or targeted kinaseinhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib,CYT387, Lestaurtinib, Pacritinib and TG101348).

Another embodiment of this invention provides a method of treatingTrypanosoma cruzi infection in a mammal, comprising administering tosaid mammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid Trypanosoma cruzi infection.

Another embodiment of this invention provides a method of treatingSjogren's syndrome in a mammal, comprising administering to said mammalin need thereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat said syndrome.

Another embodiment of this invention provides a method of treatingendometriosis in a mammal, comprising administering to said mammal inneed thereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat saidendometriosis.

Another embodiment of this invention provides a method of treatingdiabetic peripheral neuropathy in a mammal, comprising administering tosaid mammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid diabetic peripheral neuropathy.

Another embodiment of this invention provides a method of treatingprostatitis in a mammal, comprising administering to said mammal in needthereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat saidprostatitis.

Another embodiment of this invention provides a method of treatingpelvic pain syndrome in a mammal, comprising administering to saidmammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid pelvic pain syndrome.

Another embodiment of this invention provides a method of treating aneurodegenerative disease in a mammal, comprising administering to saidmammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid neurodegenerative disease.

As used herein, an “effective amount” means an amount of compound that,when administered to a mammal in need of such treatment, is sufficientto (i) treat a particular disease, condition, or disorder which can betreated with a compound of Formula I, or (ii) attenuate, ameliorate, oreliminate one or more symptoms of the particular disease, condition, ordisorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The compounds of the present invention can be used in combination withone or more additional therapeutic agents that work by the same or adifferent mechanism of action. Examples of additional therapeutic agentsinclude anti-inflammatory compounds, steroids (e.g., dexamethasone,cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin,ibuprofen, indomethacin, and ketoprofen), and opioids (such asmorphine), and chemotherapeutic agents.

Also provided herein is a pharmaceutical combination comprising aneffective amount of: (a) at least one compound of Formula I; and (b) atleast one additional therapeutic agent selected from anti-inflammatorycompounds, steroids (e.g., dexamethasone, cortisone and fluticasone),analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, andketoprofen), and opioids (such as morphine), for use in the treatment ofpain in a mammal, wherein (a) and (b) can be in separate dosage forms orin the same dosage form.

The term “pharmaceutical combination” as used herein refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that at least one of the compounds of Formula I, and at least oneadditional therapeutic agent are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that at least one of the compounds ofFormula I, and at least one additional therapeutic agent, areadministered to a patient as separate entities either simultaneously orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

Also provided herein is a method of treating pain in a mammal,comprising co-administering to a mammal in need thereof an effectiveamount of: (a) at least one compound of Formula I; and (b) at least oneadditional therapeutic agent selected from anti-inflammatory compounds,steroids (e.g., dexamethasone, cortisone and fluticasone), analgesicssuch as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen),opioids (such as morphine), calcitonin gene-related peptide receptorantagonists, subtype-selective ion channel modulators, anticonvulsants(for example Pregabalin and gabapentin), dual serotonin-norepinephrinreuptake inhibitors (for example duloxetine, venlafaxine andmilnacipran), and tricyclic antidepressants (such as amitriptyline,nortriptyline and desipramine).

Another embodiment of this invention provides a method of treatingdiseases related to an imbalance of the regulation of bone remodeling ina mammal, comprising administering to said mammal in need thereof one ormore compounds of Formula I or a pharmaceutically acceptable saltthereof in an amount effective to treat said disease. In one embodiment,the disease is osteoporosis, rheumatoid arthritis, and bone metastases.

In one embodiment, the method for treating diseases related to animbalance of the regulation of bone remodeling in a mammal comprisesadministering a TrkA inhibitor of the invention in combination with oneor more additional therapeutic agents or therapies. Examples ofadditional therapeutic agents or therapies include anti-TNF treatments(for example monoclonal antibody such as infliximab (Remicade),adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab(Simponi), or with a circulating receptor fusion protein such asetanercept (Enbrel)), antimetabolite and antifolate drug (for exampleMethotrexate), or targeted kinase inhibitors (for example JAK familyinhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritiniband TG101348).

The term “co-administering” is meant to encompass administration of theselected therapeutic agents to a single patient, and is intended toinclude treatment regimens in which the agents are administered by thesame or different route of administration or at the same or differenttimes. This term encompasses administration of two or more agents to amammal so that both agents and/or their metabolites are present in themammal at the same time. It includes simultaneous administration inseparate compositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. In some embodiments, the compound(s) of theinvention and the other therapeutic agent(s) are administered in asingle composition. In some embodiments, compound(s) of the inventionand the other agent(s) are admixed in the composition.

Also provided herein is a medicament containing a compound of Formula Ifor treatment of pain in a mammal in combination with an additionaltherapeutic agent selected from anti-inflammatory compounds, steroids(e.g., dexamethasone, cortisone and fluticasone), analgesics such asNSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), andopioids (such as morphine).

Also provided herein is a medicament containing a therapeutic agentselected from anti-inflammatory compounds, steroids (e.g.,dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs(e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids(such as morphine) for treatment of pain in a mammal in combination witha compound of Formula I.

Compounds of the invention may be administered by any convenient route,e.g. into the gastrointestinal tract (e.g. rectally or orally), thenose, lungs, musculature or vasculature, or transdermally or dermally.Compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

Another formulation may be prepared by mixing a compound describedherein and a carrier or excipient. Suitable carriers and excipients arewell known to those skilled in the art and are described in detail in,e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound described herein or pharmaceutical composition thereof) or aidin the manufacturing of the pharmaceutical product (i.e., medicament).

Accordingly, another aspect of the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier.

According to another embodiment, the present invention provides acompound of Formula I or a pharmaceutically acceptable salt thereof, foruse in the treatment of pain in a mammal. In one embodiment, the pain ischronic pain. In one embodiment the pain is acute pain. In oneembodiment, the pain is inflammatory pain, neuropathic pain, or painassociated with cancer, surgery, or bone fracture.

According to another embodiment, the present invention provides acompound of Formula I or a pharmaceutically acceptable salt thereof, foruse in the treatment of cancer in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of inflammation or an inflammatory disease or disorder in amammal. In one embodiment, the inflammatory disease is inflammatory lungdiseases (such as asthma), interstitial cystitis, bladder pain syndrome,inflammatory bowel diseases (including ulcerative colitis and Crohn'sdisease), and inflammatory skin diseases such as atopic dermatitis.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of infectious diseases, for example Trypanosoma cruziinfection, in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of Sjogren's syndrome in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of endometriosis in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of diabetic peripheral neuropathy in a mammal,

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of prostatitis in a mammal,

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of pelvic pain syndrome in a mammal,

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of a neurodegenerative disease in a mammal.

According to a further aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for the treatment of a conditionselected from pain, cancer, inflammation, neurodegenerative disease orTrypanosoma cruzi infection. In one embodiment, the condition is chronicpain. In one embodiment, the condition is acute pain. In one embodiment,the pain is inflammatory pain, neuropathic pain, or pain associated withcancer, surgery, or bone fracture. In one embodiment, the condition iscancer. In one embodiment, the condition is inflammation. In oneembodiment, the condition is a neurodegenerative disease. In oneembodiment, the condition is Trypanosoma cruzi infection. In oneembodiment, the condition is Sjogren's syndrome. In one embodiment, thecondition is endometriosis. In one embodiment, the condition is diabeticperipheral neuropathy. In one embodiment, the condition is prostatitis.In one embodiment, the condition is pelvic pain syndrome.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon (unless otherwise stated) in anhydroussolvents, and the reaction flasks were typically fitted with rubbersepta for the introduction of substrates and reagents via syringe.Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel or C-18 reverse phase column, or on asilica SepPak cartridge (Waters).

Biological Assays Example A-1 TrkA Kinase Binding Assay

TrkA binding activity was determined in a TrkA LanthaScreen™ Eu KinaseBinding Assay. 5 nM His-tagged recombinant human TrkA (6HIS taggedcytoplasmic domain from Invitrogen, Cat. No. PV3144) was incubated with4 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat. No. PV5592), 2 nMbiotinylated anti-His (Invitrogen Cat. No. PV6090), and 2 nMeuropium-labeled Streptavidin (Invitrogen Cat. No. PV5899), in buffer(25 mM MOPS, pH 7.5, 5 mM MgCl₂, 0.005% Triton X-100). Three fold serialdilutions of compounds of the invention in DMSO were added to a finalpercentage of 2% DMSO. After 60-minute incubation at 22° C., thereaction was measured using the EnVision mutlimode plate reader(PerkinElmer) via TR-FRET dual wavelength detection at 615 nM and 665nM. The percent of control was calculated using a ratiometric emissionfactor. The IC₅₀ values were determined by fitting a four parametermodel to the percent of control data.

Table A provides averaged IC₅₀ values for compounds of the inventionwhen tested in the assay of Example A, where A represents an averagedIC₅₀ value <100 nM; and B represents an averaged IC₅₀ value from 100 to1,000 nM.

TABLE A TrkA enzyme IC₅₀ Example # (nM) 1 A (Representative example) 2 B(Representative example) 3 A (Representative example) 4 A 5 A 6 B 7 A(Representative example) 8 B (Representative example) 9 B(Representative example) 10  B (Representative example) 11  A 12  A

Example A-2 p38 Kinase Binding Assay

p38a binding activity was determined in a p38a LanthaScreen™ Eu KinaseBinding Assay. 5 nM of inactive, GST-tagged recombinant human p38a(GST-tagged cytoplasmic domain from Invitrogen, Catalog No. PV3305) wasincubated with 5 nM Alexa-Fluor® Tracer 199 (Invitrogen Cat. No.PV5830), and 2 nM europium labeled anti-GST antibody (Invitrogen Cat.No. PV5594), in buffer (25 mM [Na⁺] HEPES pH 7.3, 10 mM MgCl₂, 100 μMNaVO₄). Three fold serial dilutions of compounds of the invention inDMSO were added to a final percentage of 2% DMSO. After 60-minuteincubation at 22° C., the reaction was measured using the EnVisionmultimode plate reader (PerkinElmer) via TR-FRET dual wavelengthdetection at 615 nM and 665 nM. The percent of control was calculatedusing a ratiometric emission factor. The IC₅₀ values were determined byfitting a four parameter model to the percent of control data. Thecompounds of Examples 1-12 were tested in this assay, and all compoundswere found to be 1000 fold more potent against TrkA than p38a.

Example B Off-Target Kinase Profiling

A representative compound of the invention (Example 3) was tested foroff-target kinase activity at a concentration of 10 μM by Millipore,Inc. in their KinaseProfiler™ service against all the kinases availablein their full kinase panel. The compound was run in duplicate at aconcentration of ATP near the Km for each individual kinase according toMillipore's specifications. The results are shown in Table B. Data arereported as percent of control (POC) and are the average of the tworeplicates.

In the KinaseProfiler™ the compound of Example 3 showed remarkable andunexpected selectivity for inhibiting TrkA versus other kinases in thepanel. In fact, the compound was largely inactive against off-targetkinases at a concentration of 10 μM, and thus would not be expected toinhibit off-target kinases at therapeutic doses in mammals. The abilityof compounds of the invention to selectively inhibit the Trk pathwaywithout inhibiting other off-target kinases could translate into drugprofiles that are essentially free of side-effects related to inhibitionof off-target kinases. Such a drug profile would represent a saferapproach to treating pain, inflammation, cancer and certain skindiseases than has been previously reported.

TABLE B Example 3 Kinase Avg POC Abl2 148.5 Abl-P 154.5 AKT1 103.5 AKT2219.5 AKT3 99 ALK 110 ALK4 104.5 AMPK(A1/B1/G1) 149.5 ARK5 92.5 AURKA121 Axl 117 BLK_m 108.5 Bmx 114.5 BrSK1 127 BrSK2 135 BTK 123 CAMK1103.5 CAMK1d 138 CAMK2b 96.5 CAMK2d 131 CAMK2g 112 CAMK4 147.5CDK1/cyclinB 102.5 CDK2/cyclinA 100.5 CDK2/cyclinE 106.5 CDK3/cyclinE103 CDK5/p25 108.5 CDK5/p35 110.5 CDK6/cyclinD3 107.5 CDK7/cyclinH/MAT1120.5 CDK9/cyclinT1 107.5 CHK1 108 CHK2 126.5 CK1_y 98 CK1delta 141CK1gamma1 112 CK1gamma2 109 CK1gamma3 125 CK2 96.5 CK2alpha2 102.5 CLK2135 CLK3 104 c-RAF 94.5 CSK 137.5 DAPK1 137.5 DAPK2 106 DAPK3 118.5DCAMKL2 222.5 DDR2 98 DMPK 105 DRAK1 129 DYRK2 92.5 eEF-2K 148.5 EGFR97.5 EphA1 93.5 EphA2 120 EphA3 128.5 EphA4 106.5 EphA5 116 EphA7 91EphA8 122 EphB1 122 EphB2 118.5 EphB3 63 EphB4 116 ErbB4 126 ERK1 111.5ERK2 116 FAK 105.5 FAK2 103.5 Fer 92.5 Fes 123 FGFR1 96 FGFR2 110 FGFR3116.5 FGFR4 174.5 Fgr 118 Flt1 91.5 Flt3 71 Flt4 80.5 Fms 91.5 Fyn 110GRK5 84 GRK6 105 GRK7 104.5 GSK3alpha 170 GSK3beta 195 Haspin 121 Hck110.5 HIPK1 115.5 HIPK2 101.5 HIPK3 109.5 IGF-1R 74.5 IGF-1R Activated87 IKKalpha 127 IKKbeta 123 IR 90 IR Activated 99.5 IRAK1 102.5 IRAK4131.5 IRR 99.5 ITK 128 JAK2 136.5 JAK3 117.5 JNK1alpha1 111.5 JNK2alpha299.5 JNK3 124.5 KDR 115.5 KIT 86.5 Lck 93 LIMK1 92 LKB1 95.5 LOK 97.5Lyn 98 MAP3K5 102 MAP4K2 113 MAPKAP-K2 142.5 MAPKAP-K3 128.5 MAPKAP-K5108.5 MARK1 112 MARK2 106.5 MEK1 111 MELK 115 Mer 104.5 Met 129 MINK 105MKK4_m 132.5 MKK6 132.5 MKK7beta 143.5 MKNK2 99 MLK1 100.5 MRCKalpha172.5 MRCKbeta 121.5 MSK1 152.5 MSK2 119.5 MSSK1 140 MST1 92.5 MST2102.5 MST3 146.5 mTOR 78.5 mTOR/FKBP12 92.5 MuSK 82.5 MYLK 122 NEK11 110NEK2 125.5 NEK3 105.5 NEK6 125 NEK7 118 NLK 116.5 p38alpha 93 p38beta102 p38delta 92.5 p38gamma 114.5 p70S6K 273.5 PAK2 98 PAK4 103 PAK5145.5 PAK6 167 PASK 147 PDGFRalpha 106 PDGFRbeta 175 PDK1 123 PhKgamma2115.5 Pim-1 119.5 Pim-2 117.5 Pim-3 107.5 PKAC-alpha 136.5 PKCalpha 104PKCbetaI 87 PKCbetaII 96.5 PKCdelta 98.5 PKCepsilon 98 PKCeta 94.5PKCgamma 100 PKCiota 69.5 PKCtheta 113.5 PKCzeta 103 PKD1 100.5 PKD2 115Plk1 95 Plk2 106 Plk3 115 PRK2 106.5 PRKG1alpha 108 PRKG1beta 98 PrKX188 PTK5 102 PTK6 110 Ret 89.5 RIPK2 96.5 ROCK-I 115 ROCK-II 110 Ron90.5 Ros 97 Rse 106.5 Rsk1 123 Rsk2 134 Rsk3 104.5 Rsk4 99 SGK1 276.5SGK2 159.5 SGK3 133 SIK 154.5 SRC 102.5 SRPK1 111 SRPK2 112.5 STK33107.5 Syk 101 TAK1 94 TAO1 119 TAO2 108 TAO3 94 TBK1 103 TEC Activated144.5 Tie2 121.5 TLK2 108.5 TNK2 118.5 TrkA 0.5 TrkB 95 TSSK1 83.5 TSSK2132.5 Txk 139.5 ULK2 98 ULK3 90.5 VRK2 96.5 WNK2 120 WNK3 108 Yes 114ZAP-70 135

Preparation of Synthetic Intermediates Intermediate 1

1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine Step A: ethyl1-methyl-1H-pyrazole-4-carboxylate

To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate(100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL). Thereaction was cooled in an ice bath to 5° C., and then methylhydrazine(35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observedduring hydrazine addition and the temperature was kept below 12° C. bycontrolling the addition rate. After the hydrazine addition wascomplete, the ice bath was removed, and the reaction was allowed to stirat ambient temperature for 16 hours. The reaction was concentrated invacuo and the residue dissolved in DCM and re-concentrated, then driedfor 2 days to yield ethyl 1-methyl-1H-pyrazole-4-carboxylate (106 g, 99%yield) as a tan orange oil. MS (apci) m/z=155.1 (M+H).

Step B: 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

To a four-necked 5-liter round bottomed flask fitted with an overheadstirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.0Min THF). The solution was cooled in an acetone/dry ice bath first(internal temperature of −79° C.) under nitrogen, followed by slowaddition of propiononitrile (103 mL, 1444 mmol) via dropping funnel. Themixture was stirred at −80° C. for 90 minutes. A solution of ethyl1-methyl-1H-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF(500 mL) was then introduced dropwise via an addition funnel (additiontime: about 45 minutes; internal temperature during addition remainedbelow −76° C.). After the addition was complete, the reaction wasallowed to slowly warm to ambient temperature and stirred overnight. Anorange glass deposited on the bottom of the flask. The organics weredecanted and the glass was dissolved in warm water. The mixture waswashed with ether (3×1000 mL) The aqueous phase was then pH-adjusted to5 (pH paper) using concentrated HCl and saturated bicarbarbonatesolution The aqueous layer was extracted with DCM (3×1000 mL). Thecombined organic extracts were dried over MgSO₄ filtered andconcentrated to yield2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile as an amberoil (92 g, 82% yield). MS (apci) m/z=162.1 (M−H).

Step C: 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine

A 3 L, 3 necked round bottomed flask was charged with2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile (60 g, 368mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazinehydrochloride (58 g, 404 mmol) at ambient temperature to form ayellowish suspension. The reaction vessel was equipped with a watercondenser and refluxed (using a heating mantle) overnight. The reactionwas concentrated and 1M NaOH (1 L) was added and the solid was broken upand collected. The solid was washed with water and hexanes. A secondcrop crashed out in the filtrate and was collected. The combined solidswere crushed and triturated with ether (500 mL). The solid was collectedby filtration, washed with hexanes and dried in vacuo to provide thetitle compound (93 g, 100% yield) as a yellow solid. MS (apci) m/z=254.1(M+H).

Intermediate 2

phenyl (1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate

A 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine [Intermediate 1](50 g, 197.4 mmol) and EtOAc (1000 mL) to obtain a clear brownishsolution. To this was added NaOH (2M aq) (500 mL) in one portion toobtain a turbid mixture (the aqueous and organic layers were clear, buta precipitate was observed in between the two layers). After 3 minutes,phenyl carbonochloridate (74.29 mL, 592.2 mmol) was added slowly atambient temperature (the temperature of the reaction mixture increasedto 33° C. during the addition). The reaction stirred at ambienttemperature for 2 hours. Additional phenyl carbonochloridate (10 mL) wasadded. After 30 minutes the organics layers were separated, washed withbrine and concentrated in vacuo. The residue was purified by silicacolumn chromatography eluting with 75% EtOAc/hexanes to provide thetitle compound (60 g, 81% yield) as a cream foam. MS (apci) m/z=374.1(M+H).

Intermediate 3

5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate StepA: Preparation of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one

A mixture of ethyl 2-cyanopropanoate (50.5 g, 397.2 mmol) andphenylhydrazine (39 mL, 397.2 mmol) in dioxane (100 mL) was heated at110° C. for 5 days. The cooled mixture was concentrated to ½ volume thencooled in ice and triturated with cold Et₂O. Solids were filtered,washed extensively with Et₂O and dried in vacuo to afford5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (34.69 g, 46% yield) as afluffy white powder. MS (apci) m/z=190.1 (M+H).

Step B: Preparation of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yltrifluoromethane sulfonate

A suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (13.72 g,72.5 mmol) and N-phenylbis(trifluoromethylsulfonamide) (27.2 g, 76.1mmol) in DMF (100 mL) was treated with DIEA (37.9 mL, 217.5 mmol) andthe mixture stirred at ambient temperature for 16 hours. The mixture waspartitioned between sat. NaHCO₃ (400 mL) and EtOAc (200 mL) and theaqueous layer was extracted with EtOAc (2×200 mL). The combined organicphases were washed with water (5×50 mL) and brine (50 mL) then driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with 4:1 hexanes/EtOAc,to afford the title compound (23.1 g, 99% yield) as a pale yellow solid.MS (apci) m/z=322.0 (M+H).

Intermediate 4

3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one[Intermediate 3, step A] (1.60 g, 8.46 mmol) in acetonitrile (30 mL) wasadded phosphorus oxybromide (3.64 g, 12.7 mmol) in one portion. Themixture was stirred at reflux for 3 hours then cooled and concentratedin vacuo. The residue was treated with DCM (50 mL) then sat. NaHCO₃ (50mL) was slowly added. The mixture was stirred for 30 minutes then thelayers separated and the aqueous layer extracted with DCM (2×50 mL). Thecombined organic phases were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica column chromatography eluting with 2:1 hexanes/EtOAc, to affordthe title compound (273 mg, 13% yield) as a white solid. MS (apci)m/z=254.0 (M+H).

Intermediate 5

5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one

3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine [Intermediate 4] (763 mg,3.03 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)one(1.42 g, 6.05 mmol), K₂CO₃ (1.67 g, 12.1 mmol) and Pd(PPh₃)₄ (350 mg,0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5mL) and warmed to 95° C. in a sealed tube for 16 hours. The cooledmixture was filtered and the filtrate partitioned between water (30 mL)and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL)and the combined organic phases were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with 2% MeOH/DCM toafford the title compound (504 mg, 59% yield) as a yellow foam. MS(apci) m/z=281.2 (M+H).

Intermediate 6

phenyl(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate

To a suspension of5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one[Intermediate 5] (2.80 g, 9.99 mmol) in EtOAc (120 mL) was added 2N NaOH(14.98 mL, 29.97 mmol) followed by phenyl chloroformate (2.5 mL, 19.98mmol). The mixture was stirred at ambient temperature for 16 hours thenpartitioned between water (100 mL) and EtOAc (100 mL) and the aqueouslayer extracted with EtOAc (2×50 mL). The combined organic phases werewashed with sat. NaHCO₃ (50 mL) and brine (50 mL) then dried overNa₂SO₄, filtered and concentrated to afford the title compound as a paleyellow syrup which was used directly without purification, assuming 100%yield. MS (apci) m/z=401.2 (M+H).

Intermediate 7

4-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one

Prepared according to the procedure of Intermediate 5, replacing3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine with5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate[Intermediate 3] and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)onewith1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.The product was purified by silica column chromatography eluting with 2%MeOH/DCM to afford the title compound (160 mg, 37% yield) as a pinksolid. MS (apci) m/z=281.1 (M+H).

Intermediate 8

phenyl(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the procedure of Intermediate 6, replacing5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-onewith4-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one.MS (apci) m/z=401.1 (M+H).

Intermediate P107 (Representative Intermediate)

3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of2,4-dimethyl-3-oxopentanenitrile

To a solution of propiononitrile (518 mg, 9.40 mmol) in THF (50 mL, 7.83mmol) at −78° C. under N₂ was slowly added lithiumbis(trimethylsilyl)amide (1M in THF) (7.83 mL, 7.83 mmol). After 30minutes, methyl isobutyrate (0.898 mL, 7.83 mmol) was added dropwise,and the reaction mixture was warmed to 0° C. A yellow precipitateformed, the reaction mixture was stirred for 1 hour, then diluted withH₂O (50 mL) to dissolve the solids. The mixture was extracted with Et₂O(25 mL), and the basic aqueous phase was acidified with 2M HCl (5 mL)and extracted with Et₂O (2×50 mL). The combined organic phases werewashed with brine (50 mL), dried with MgSO₄, filtered, and concentratedto afford the product (421 mg, 42.9% yield)

Step B: Preparation of 3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with 2,4-dimethyl-3-oxopentanenitrileto yield the product as a yellow syrup (0.587 g, 81.1% yield). MS (apci)m/z=216.2 (M+H).

Intermediate P109 (Representative Intermediate)

3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of4-methoxy-3-oxobutanenitrile

To a solution of methyl 2-methoxyacetate (0.4753 mL, 4.803 mmol) in THF(20 mL, 4.803 mmol) at −78° C. under N₂ was added acetonitrile (0.3033mL, 5.763 mmol), followed by lithium bis(trimethylsilyl)amide (1M inTHF) (4.803 mL, 4.803 mmol). After stirring 1 hour, the reaction mixturewas warmed to 0° C. and stirred for 1 hour. The reaction mixture wasthen diluted with H₂O (25 mL), washed with Et₂O (25 mL), thenneutralized with 2 M HCl (1.5 mL). This was extracted with Et₂O (2×25mL) and the combined organic phases were washed with brine (25 mL),dried with MgSO₄, filtered, and concentrated to afford the product (169mg, 31.1% yield). ¹H NMR (CDCl₃) δ 4.09 (s, 2H), 3.66 (s, 21-1), 3.46(s, 3H)

Step B: Preparation of 3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with 4-methoxy-3-oxobutanenitrile toyield the product as a pale yellow residue (6.0 mg, 2.0% yield). MS(apci) m/z=204.0 (M+H).

Intermediate P134

1,4-dimethyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P107, substitutingmethyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylateto afford 2-methyl-3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In StepB, phenylhydrazine was replaced by methylhydrazine to afford the titlecompound. MS (apci) m/z=204.1 (M+H).

Intermediate 151

1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine Step A:Preparation of methyl 1-methyl-1H-1,2,4-triazole-3-carboxylate

To a stirred suspension of NaH (60% oil dispersion, 0.346 g, 8.66 mmol)in DMF (20 mL) was added dropwise a solution of methyl1H-1,2,4-triazole-3-carboxylate (1.00 g, 7.87 mmol) in DMF (20 mL) at 0°C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour.MeI (0.982 mL, 15.7 mmol) was added dropwise. The reaction mixture wasstirred at ambient temperature overnight. The reaction was poured intocold water and extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified bycolumn chromatography (3:1 hexanes/EtOAc) to give the title compound(0.380 g, 34% yield) as a white solid. MS (apci) m/z=142.1 (M+H).

Step B: Preparation of1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]5-amine

Prepared according to the method described for Intermediate P109, usingmethyl 1-methyl-1H-1,2,4-triazole-3-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A. MS (apci) m/z=255.1 (M+H).

Intermediate 152

1′-(2-methoxyethyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine

Prepared according to the method described for Intermediate P109, usingethyl 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A.

Intermediate 155

4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation of ethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate

A mixture of ethyl 2H-1,2,3-triazole-4-carboxylate (2.00 g, 14.2 mmol),K₂CO₃ (3.53 g, 25.5 mmol) and methyl iodide (3.54 mL, 56.7 mmol) inacetonitrile (40 mL) was stirred at 50° C. under nitrogen overnight.After cooling to ambient temperature, the mixture was filtered throughCelite®. The filtrate was concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (4:1 hexane/EtOAc) togive the title compound (0.780 g, 35% yield). MS (apci) m/z=156.0 (M+H).

Step B: Preparation of4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl

1H-pyrazol-5-amine: Prepared according to the method described forIntermediate P109 using ethyl 2-methyl-2H-1,2,3-triazole-4-carboxylateas a replacement for methyl 2-methoxyacetate, and substitutingpropionitrile for acetonitrile in Step A. MS (apci) m/z=254.9 (M+H).

Intermediate 171 (Representative Example)

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170,1.52 mg, 6.21 mmol) in THF (12 mL) and MeOH (6 mL) was added LiOH (2Maq, 9.31 mL, 18.6 mmol). The reaction mixture was stirred at ambienttemperature for 19 hours, then partially concentrated under reducedpressure, then neutralized with 6M HCl (3.2 mL), extracted with 10:90MeOH/DCM (3×25 mL), and the combined organic extracts were washed withbrine (50 mL), dried (MgSO₄), filtered and concentrated to give thetitle compound as a yellow solid (1.3 g, 96% yield) MS (apci) m/z=218.1(M+H).

Intermediate 175

4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation ofN′-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(Intermediate 171, 93 mg, 0.428 mmol) in DCM (5 mL) and DIEA (0.149 mL,0.856 mmol) was added isobutyl carbonochloridate (0.061 mL, 0.471 mmol).The reaction mixture was stirred at ambient temperature for 1 hour, thenacetohydrazide (48 mg, 0.642 mmol) was added. The reaction mixture wasstirred at ambient temperature for 18 hours, then diluted with H₂O (10mL), extracted DCM (2×10 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure to afford the product as a pale yellow solid (119mg, 101% yield). MS (apci) m/z=274.1 (M+H).

Step B: Preparation of4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amine

A mixture ofN′-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide (117mg, 0.428 mmol) and POCl₃ (0.5 mL) was heated in a pressure tube to 90°C. for 1 hour. The reaction mixture was transferred to a separatoryfunnel with EtOAc (5 mL), then diluted with saturated aqueous NaHCO₃ (20mL), extracted with EtOAc (2×15 mL), dried (MgSO₄), filtered andconcentrated. The residue was purified by silica column chromatographyeluting with 0-75% acetone/hexanes to afford the title compound as ayellow solid (19.6 mg, 18% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 176

4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine

To a suspension of NaH (60% in mineral oil, 36 mg, 0.897 mmol) in THF (5mL) under N₂ was added N-hydroxyacetimidamide (66 mg, 0.897 mmol). Thereaction mixture was heated to reflux for 1 hour, then cooled to ambienttemperature and ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170,200 mg, 0.815 mmol) was added. The reaction mixture was heated to refluxfor 18 hours, then cooled to ambient temperature and additional NaH (60%in mineral oil, 18 mg, 0.449 mmol) was added. The reaction mixture washeated to reflux for 4 hours, then diluted with H₂O (10 mL), extractedDCM (2×15 mL), and the combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified by silica column chromatography eluting with 0-50%acetone/hexanes to afford the title compound as an orange solid (84 mg,40% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 178

4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amineStep A: Preparation of 2,2,2-trifluoro-N′-hydroxyacetimidamide

To a suspension of hydroxylamine hydrochloride (5.45 g, 78.4 mmol) inMeOH (100 mL) was added NaOMe (25 wt % solution in MeOH, 17.9 mL, 78.4mmol) and the mixture stirred at ambient temperature for 10 minutes,then filtered and the solid was washed with MeOH. The filtrate wascooled to 0° C. and then 2,2,2-trifluoroacetonitrile (7.45 g, 78.4 mmol)gas was bubbled into the solution over 30 minutes. The reaction mixturewas then allowed to warm to ambient temperature for 19 hours. Thesolution was concentrated under reduced pressure to 50 mL and the solidswere filtered. The filtrate was concentrated, re-suspended in cold MeOH,and filtered. The filtrate was concentrated, again re-suspended in coldMeOH, and filtered. The filtrate was concentrated to give the product asa waxy white solid (6.7 g, 67% yield). ¹H NMR (CD₃CN) δ 8.32 (s, 1H),5.25 (br s, 2H). ¹⁹F NMR (CD₃CN) 8-71.8 (s).

Step B: Preparation of4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amine

To a suspension of NaH (60% in mineral oil, 356 mg, 0.897 mmol) in THF(5 mL, 0.815 mmol) under N₂ was added2,2,2-trifluoro-N′-hydroxyacetimidamide (115 mg, 0.897 mmol). Thereaction mixture was heated to reflux for 1 hour, then cooled to ambienttemperature and powdered 4 A molecular sieves (200 mg) and ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170;200 mg, 0.815 mmol) were added and heated to reflux. The reactionmixture was heated to reflux for 18 hours, then filtered, diluted withH₂O (15 mL), extracted DCM (2×25 mL), and the combined organic extractswere washed with brine (25 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure. The residue was purified by silica columnchromatography eluting with 0-50% acetone/hexanes to afford the titlecompound as a white solid (44 mg, 17% yield). MS (apci) m/z=310.1 (M+H).

Intermediate 189 (Representative Example)

1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine Step A:3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile

A 1M solution of LHMDS in dry THF (26.3 mL, 26.3 mmol) was cooled to−78° C. and acetonitrile (1.43 mL, 27.5 mmol) was added dropwise over 2minutes. The mixture was stirred at −78° C. for 1 hour and a solution ofmethyl tetrahydro-2H-pyran-4-carboxylate (3.41 mL, 25.0 mmol) in dry THF(12 mL) was added. The mixture was stirred for 1 hour, the dry ice bathwas removed and the mixture allowed to reach ambient temperature. Themixture was poured into chilled H₂O (250 mL) and was extracted with Et₂O(3×). The aqueous portion was cooled to 0° C. and 6M HCl was addeddropwise to pH=3 (starting pH=12). The mixture was extracted with EtOAc(3×) and the combined extracts were dried over MgSO₄. The solutioneluted through a SiO₂ plug eluting with EtOAc. The filtrate wasconcentrated to give the title compound as a colorless oil (2.52 g,66%). ¹H NMR (CDCl₃) δ 3.99-4.06 (m, 2H), 3.54 (s, 211), 3.46 (t, 2H),2.76-2.86 (m, 1H), 1.70-1.86 (m, 4H).

Step B: 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

To a solution of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (2.30g, 12.8 mmol) in absolute EtOH (35 mL) was added phenylhydrazinehydrochloride (2.21 g, 15.3 mmol) and the mixture was heated at refluxuntil complete by TLC (5 hours). The mixture was cooled to ambienttemperature and was concentrated. The residue was partitioned in H₂O (75mL) and EtOAc (40 mL). 2M NaOH was added to pH=5 with vigorous mixing,the organic layer was removed and the aqueous was extracted with EtOAc(2×). The combined EtOAc fractions were washed with H₂O and saturatedNaCl. The solution was diluted with an equal volume of hexanes, driedover MgSO₄/activated carbon and eluted through a SiO₂ plug eluting with50% EtOAc-hexanes. The filtrate was concentrated to give a gold syrup.The syrup was treated with Et₂O and stirred until a fine, granularsuspension formed. The solid was collected, washed with Et₂O and driedin vacuum to furnish the title compound as a white solid (2.01 g, 65%).¹H NMR (CDCl₃) δ 7.55 (d, 2H), 7.46 (t, 2H), 7.32 (t, 1H), 5.49 (s, 1H),4.00-4.08 (m, 2H), 3.97 (br s, 2H), 3.52 (dt, 2H), 2.86 (m, 1H)1.73-1.93 (m, 4H).

The following compound was prepared according to the method used for thepreparation of 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine(Intermediate 189) using either acetonitrile or propiononitrile in StepA in conjunction with the appropriate ester.

Inter- mediate # Structure Data 193

¹H NMR (CDCl₃) δ 7.60 (d, 2H), 7.49 (t, 2H), 7.37 (t, 1H), 6.45 (s, 1H),3.67 (br s, 2H), 2.45 (s, 3H), 2.24 (s, 3H).

Intermediate 199

Phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate StepA: ethyl 1-methyl-1H-pyrazole-4-carboxylate

To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate(100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) toobtain a clear yellowish solution. The reaction was cooled in an icebath to 5° C., and then methylhydrazine (35.8 mL, 680 mmol) was addeddropwise. A vigorous exotherm was observed during hydrazine addition andthe temperature was kept below 12° C. by controlling the addition rate.After the hydrazine addition was complete, the ice bath was removed, andthe reaction was allowed to stir at ambient temperature overnight. Thereaction was concentrated on a rotary evaporator to a crude orange oil.The crude was taken up in DCM and re-concentrated, then on high vacuumfor 2 days to yield tan orange oil. LC/MS and ¹H NMR showed essentiallypure ethyl 1-methyl-1H-pyrazole-4-carboxylate (106 g, 99.1%).

Step B: 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

To a four-necked 5-liter round bottomed flask fitted with an overheadstirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.0Min THF). The solution was cooled in an acetone/dry ice bath first(internal temperature of −79° C.) under nitrogen, followed by slowaddition of propiononitrile (103 mL, 1444 mmol) via dropping funnel. Themixture was stirred at −80° C. for 90 minutes. A solution of ethyl1-methyl-1H-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF(500 mL) was then introduced dropwise via an addition funnel (additiontime: about 45 minutes; internal temperature during addition remainedbelow −76° C.). After the addition was complete, the reaction wasallowed to slowly warm to ambient temperature and stirred overnight. Anorange glass deposited on the bottom of the flask. The organics weredecanted and the glass was dissolved in warm water. The mixture waswashed with ether (3×1000 mL). The aqueous phase was then pH-adjusted to5 (pH paper) using concentrated HCl and saturated bicarbarbonatesolution The aqueous layer was extracted with DCM (3×1000 mL) Thecombined organic extracts were dried over MgSO₄ filtered andconcentrated to yield the2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile as an amberoil (92 g, 82%). MS (apci) m/z=162.1 (M−H).

Step C: 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine

A 3 L, 3 necked round bottomed flask was charged with2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile (60 g, 368mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazinehydrochloride (58 g, 404 mmol) at ambient temperature to form ayellowish suspension. The reaction vessel was equipped with a watercondenser and refluxed (using a heating mantle) overnight. The reactionwas concentrated and 1M NaOH (1 L) was added and the solid was broken upand collected. The solid was washed with water and hexanes. A secondcrop crashed out in the filtrate and was collected. The combined solidswere crushed and triturated with ether (500 mL). The solid was collectedfiltration, washed with hexanes and air dried under vacuum to provide1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (93 g, 100%).

Step D: phenyl1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate

In a 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(both the aqueous and organic layers were clear but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature exotherm to 33° C. The reaction stirred at ambienttemperature for 2 hours. Additional phenyl carbonochloridate (10 mL) wasadded. After 30 minutes the organics were separated, washed with brineand concentrated in vacuo. The product was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (60 g,81.4%).

Intermediate 200

phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate

A 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(the aqueous and organic layers were clear, but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature (the temperature of the reaction mixture increased to 33° C.during the addition). The reaction stirred at ambient temperature for 2hours. Additional phenyl carbonochloridate (10 mL) was added. After 30minutes the organics layers were separated, washed with brine andconcentrated in vacuo. The residue was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (60 g,81.4%).

The following compounds were prepared according to the method describefor the preparation of Intermediate 200, using the appropriate aminopyrazole intermediate.

Intermediate # Structure Name Data 214

phenyl (4- methyl-3-(5- methyl-1,3,4- oxadiazol-2-yl)- 1-phenyl-1H-pyrazol-5- yl)carbamate MS (apci) m/z = 376.1 (M + H). 215

phenyl 4-methyl- 3-(3-methyl- 1,2,4-oxadiazol- 5-yl)-1-phenyl-1H-pyrazol-5- ylcarbamate MS (apci) m/z = 376.1 (M + H). 216

phenyl 4-methyl- 1-phenyl-3-(3- (trifluoromethyl)- 1,2,4-oxadiazol-5-yl)-1H- pyrazol-5- ylcarbamate MS (apci) m/z = 430.1 (M + H). 220

phenyl (4- methyl-3-(5- methylisoxazol- 3-yl)-1-phenyl- 1H-pyrazol-5-yl)carbamate ¹H NMR (CDCl₃) δ 7.54 (d, 2H), 7.49 (t, 2H), 7.41 (t, 1H),7.33 (br s, 2H), 7.20 (br s, 1H), 7.08 (br s, 1H), 6.74 (br s, 1H), 6.66(br s, 1H), 6.48 (s, 1H), 2.45 (s, 3H) 2.34 (s, 3H)

Intermediate 245

5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine Step A:2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine

To a solution of 2-hydrazinylpyrazine (0.485 g, 4.40 mmol) in HOAc (6mL) was added (2-(hydroxyimino)-1-phenylbutane-1,3-dione (0.765 g, 4.00mmol) in small portions over 2 minutes. The mixture was stirred for 5minutes and the resulting light orange suspension was stirred at 60° C.for 6 hours. EtOH (1 mL) was added and the mixture was heated at 60° C.for an additional 6 hours. The resulting dark green suspension wascooled to ambient temperature and the mixture was diluted with H₂O (30mL). The green suspension was stirred for 1 hour and the solid wascollected via vacuum filtration. The collected solid was washed with H₂Oand dried in vacuum. The solid was suspended in EtOH (25 mL) andconcentrated HCl (500 μL) was added. The mixture was heated at refluxfor 20 hours, cooled to ambient temperature and diluted with chilled H₂O(75 mL). The mixture was treated with 1M NaOH to pH=7 and was extractedwith Et₂O (3×). The combined extracts were washed with saturated NaCland dried over MgSO₄. The dried solution was filtered through packedCelite® and concentrated. The residual green-yellow solid was purifiedon a SiO₂ column using step gradient elution (25% CH₂Cl₂, 50%EtOAc/hexanes) to furnish the title compound as a turquoise solid (325mg, 31%). MS (apci) m/z=266.1 (M+H).

Step B: 5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine

To a mixture of 2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine(325 mg, 1.04 mmol) and Zn dust (340 mg, 5.21 mmol) in EtOH (10 mL) wasadded concentrated HCl (95.5 μL, 1.15 mmol). The mixture was stirred atambient temperature for 17 hours, then at 65° C. for 3 hours. Themixture was cooled to ambient temperature and was filtered throughpacked Celite® eluting with MeOH. The eluent was concentrated, and theresidue was treated with H₂O and mixed. The resulting orange suspensiontreated with 2M HCl to pH=1 and the mixture was extracted with Et₂O(3×). The aqueous portion was treated with 2M NaOH to pH=8 and extractedwith EtOAc (3×). The combined EtOAc extracts were washed with saturatedNaCl and dried over MgSO₄/activated carbon. The solution was elutedthrough a SiO₂ plug eluting with EtOAc. The eluent was concentrated togive the title compound as a light yellow wax (33 mg, 13%). MS (esi)m/z=252.2 (M+H).

Intermediate 246

1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine Step A:1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole

To a solution of methylhydrazine (0.484 g, 10.5 mmol) in HOAc (10 mL)was added 2-(hydroxyimino)-1-phenylbutane-1,3-dione (2.01 g, 10.5 mmol)in small portions over 5 minutes. The reaction mixture was heated at 60°C. for 1 hour and was cooled to ambient temperature. Et₂O (50 mL) andH₂O (10 mL) were added to the mixture followed by slow addition ofsaturated Na₂CO₃ until pH=8 was obtained. The organic layer was removedand the aqueous layer was extracted with Et₂O (2×). The combined organicfractions were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel chromatography (1:5 EtOAc/hexanes) to givethe title compound as a green solid (1.32 g, 63%). MS (apci) m/z=202.1(M+H).

Step B: 1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine

To a solution of 1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole (1.32 g,6.60 mmol) in MeOH (50 mL) was added Pd(OH)₂ on carbon (200 mg, 20 wt %,0.286 mmol) and the reaction mixture was shaken under 50 psi of H₂ for 3hours at ambient temperature. The reaction mixture was evacuated, purgedwith N₂ filtered through a pad of Celite® with MeOH elution. The eluentwas concentrated and the residue dried in vacuum to provide the titlecompound as a tan solid (1.23 g, 100%). MS (apci) m/z=188.1 (M+H).

Intermediate A

3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A:5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one

A mixture of ethyl 2-cyanopropanoate (50.5 g, 397.2 mmol) andphenylhydrazine (39 mL, 397.2 mmol) in dioxane (100 mL) was heated at110° C. for 5 days. The cooled mixture was concentrated to ½ volume,then cooled in ice and triturated with cold Et₂O. The resulting solidswere filtered, washed extensively with Et₂O and dried under vacuum toafford 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (34.69 g, 46%yield) as a fluffy white powder. MS (apci) m/z=190.1 (M+H).

Step B: 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate

A suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (13.72 g,72.5 mmol) and N-phenylbis(trifluoromethylsulfonamide) (27.2 g, 76.1mmol) in DMF (100 mL) was treated with DIEA (37.9 mL, 217.5 mmol) andthe mixture was stirred at ambient temperature for 16 hours. The mixturewas partitioned between saturated NaHCO₃ and EtOAc and the aqueous layerwas extracted with EtOAc. The combined organic phases were washed withwater and brine (50 mL), then dried over Na₂SO₄, filtered andconcentrated under vacuum The residue was purified by silica columnchromatography eluting with 4:1 hexanes/EtOAc, to afford the titlecompound (23.1 g, 99% yield) as a pale yellow solid. MS (apci) m/z=322.0(M+H).

Step C: Preparation of3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate(7.5 g, 23.3 mmol), (2-methoxypyrimidin-5-yl)boronic acid (5.39 g, 35.0mmol), K₂CO₃ (12.9 g, 93.4 mmol) and Pd(PPh₃)₄ (2.7 g, 2.33 mmol) werecombined in toluene (40 mL), water (20 mL) and EtOH (10 mL) and warmedto 95° C. in a sealed tube for 18 hours. The cooled mixture was filteredthrough GF paper and the filtrate was partitioned between water (200 mL)and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2×100mL) and the combined organic phases were washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica column chromatography eluting with 1% MeOH/DCM toafford 3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine(4.3 g, 46% yield) as a foam. MS (apci) m/z=282.1 (M+H).

Intermediate B

3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amineStep A: 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one

A mixture of ethyl 2-cyanopropanoate (50.5 g, 397.2 mmol) andphenylhydrazine (39 mL, 397.2 mmol) in dioxane (100 mL) was heated at110° C. for 5 days. The cooled mixture was concentrated to ½ volume,then cooled in an ice bath and triturated with cold Et₂O. The resultingsolids were filtered, washed extensively with Et₂O and dried undervacuum to afford 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (34.69g, 46% yield) as a fluffy white powder. MS (apci) m/z=190.1 (M+H).

Step B:3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (500 mg,2.643 mmol) in DMF (5 mL) were added K₂CO₃ (730 mg, 5.285 mmol) then(2-bromoethoxy)(tert-butyl)dimethylsilane (1.134 mL, 5.285 mmol). Thereaction mixture was heated to 60° C. for 17 hours, then cooled toambient temperature. The reaction mixture was filtered, diluted withEtOAc (60 mL), washed with water and brine, dried (MgSO₄), filtered andconcentrated. The crude product was purified by silica columnchromatography eluting with 0-40% acetone/hexane, to afford the titlecompound (388 mg, 42% yield) as a waxy off-white solid. MS (apci)m/z=348.2 (M+H).

Synthetic Examples Example 1 Representative Compound

1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

To a solution of phenyl(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate(Intermediate 2, 50 mg, 0.134 mmol) in DMF (0.6 mL) were added3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine (Oakwood, 26.7 mg, 0.134 mmol)and DIEA (0.047 mL, 0.268 mmol). The reaction mixture was stirred at 60°C. for 2 days. The reaction mixture was purified by silica columnchromatography, eluting with 0-90% acetone in hexanes to afford thetitle compound as a white solid (11.3 mg, 18% yield). MS (apci)m/z=479.2 (M+H).

Example 2 Representative Compound

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 1, replacing3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine with3-methyl-1-phenyl-1H-pyrazol-5-amine (Aldrich, 23.2 mg, 0.134 mmol). Thereaction mixture was purified by reverse-phase column chromatography,eluting with 0-90% acetonitrile/water, to afford the title compound as awhite solid (7.6 mg, 13% yield). MS (apci) m/z=453.2 (M+H).

Example 3 Representative Compound

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 1, replacing3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine with1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (Chem-Impex, 30.4 mg,0.134 mmol). The reaction mixture was purified by reverse-phase columnchromatography, eluting with 0-90% acetonitrile/water, to afford thetitle compound as a white solid (7.5 mg, 11% yield). MS (apci) m/z=507.2(M+H).

Example 4

1-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 3, replacing phenyl(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate withphenyl(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate(Intermediate 6, 50 mg, 0.125 mmol). The reaction mixture was purifiedby silica column chromatography, eluting with 0-80% acetone in hexanes,to afford the title compound as a white solid (7.1 mg, 11% yield). MS(apci) m/z=534.2 (M+H).

Example 5

1-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 4, replacing phenyl(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)carbamatewith phenyl(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate(Intermediate 8, 50 mg, 0.125 mmol). The reaction mixture was purifiedby reverse-phase column chromatography, eluting with 5-70%acetonitrile/water, to afford the title compound as a white solid (1.0mg, 2% yield). MS (apci) m/z=534.2 (M+H).

Example 6

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(4-methyl-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureaStep A: Preparation of 4,4,4-trifluoro-2-methyl-3-oxobutanenitrile

To a solution of lithium bis(trimethylsilyl)amide (1M in THF, 14.78 ml,14.78 mmol) in THF (40 mL) under N₂ at −78° C. was added propiononitrile(0.983 mL, 16.89 mmol) dropwise over 2 minutes. The reaction mixture wasstirred at −78° C. for 90 minutes, then ethyl 2,2,2-trifluoroacetate(1.68 mL, 14.08 mmol) was added dropwise over 5 minutes. The reactionmixture was stirred at −78° C. for 30 minutes, then stirred at 0° C. for1 hour, then diluted with H₂O (100 mL) and extracted with Et₂O (100 mL).The aqueous phase was neutralized with 2M aq. HCl (7 mL), then extractedwith Et₂O (3×100 mL). The combined organic phases were washed with brine(100 mL), dried over MgSO₄, filtered and partially concentrated toafford the product as a pale yellow oil (3.93 g, 184% yield) containingEt₂O and THF, which was used in the following step without furtherpurification. ¹H NMR (CDCl₃) δ 3.76 (m, 6H, THF), 3.48 (q, 0.5H, Et₂O),3.20 (q, 1H, product), 1.86 (m, 6H, THF), 1.50 (d, 3H, product), 1.21(t, 0.8H, Et₂O).

Step B: Preparation of4-methyl-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine

To 4,4,4-trifluoro-2-methyl-3-oxobutanenitrile (containing THF and Et₂O,assuming theoretical mass of 2127 mg, 14.08 mmol) were added EtOH (50mL) and phenylhydrazine hydrochloride (2036 mg, 14.08 mmol). Thereaction mixture was heated to reflux for 18 hours, then concentrated,diluted with sat. aq. NaHCO₃ (100 mL), extracted with DCM (3×100 mL),and the combined organic phases were washed with brine (100 mL), driedover MgSO₄, filtered and concentrated. The crude product was purified bysilica column chromatography, eluting with 0-25% acetone in hexanes, toafford the title compound as a peach solid (2.30 g, 68% yield over 2steps). MS (apci) m/z=242.1 (M+H).

Step C: Preparation of1-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

To a solution of4-methyl-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (32.3 mg, 0.134mmol) in DIEA (0.047 mL, 0.268 mmol) and DMF (0.6 mL) was added phenyl(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate(Intermediate 2, 50 mg, 0.134 mmol). The reaction mixture was stirred atambient temperature for 14 hours. The reaction mixture was purified bysilica column chromatography, eluting with 0-85% acetone in hexanes toafford the title compound as a white solid (12.3 mg, 18% yield). MS(apci) m/z=521.2 (M+H).

Example 7 Representative Compound

1-(3-(2,2-difluorocyclopropyl)-1-phenyl-1H-pyrazol-5-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)ureaStep A: Preparation of phenyl 2,2-difluorocyclopropanecarboxylate

To a solution of 2,2-difluorocyclopropanecarboxylic acid (Aldrich, 1.00g, 8.19 mmol) in DCM (41 mL) cooled to 0° C. were added DMF (0.3 mL) andoxalyl dichloride (1.39 mL, 16.4 mmol). The reaction mixture was stirredat ambient temperature for 1 hour, then cooled to 0° C., and a solutionof phenol (0.925 g, 9.83 mmol) and DIEA (4.28 mL, 24.6 mmol) in DCM (10mL) was added slowly. The reaction mixture was slowly warmed to ambienttemperature and stirred for 2 hours, then was diluted with DCM (20 mL)and sat. aq. NaHCO₃ (60 mL) The phases were separated and the aqueousphase was extracted with DCM (3×70 mL), and the combined organic phaseswere dried over MgSO₄, filtered and concentrated. The crude product waspurified by silica column chromatography, eluting with 0-50% acetone inhexanes to afford the title compound as an amber syrup (391 mg, 24%yield). ¹H NMR (CDCl₃) δ 7.39 (t, 2H), 7.25 (t, 1H), 7.11 (d, 2H), 2.68(m, 1H), 2.20 (m, 1H), 1.89 (m, 1H).

Step B: Preparation of1-(3-(2,2-difluorocyclopropyl)-1-phenyl-1H-pyrazol-5-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared according to the procedure of Example 6, replacing ethyl2,2,2-trifluoroacetate with phenyl 2,2-difluorocyclopropanecarboxylate(391 mg, 1.97 mmol) and replacing propionitrile with acetonitrile (0.124mL, 2.17 mmol) in Step A, to afford the title compound as a white solid(26.7 mg, 10% yield). MS (apci) m/z=515.2 (M+H).

Example 8 Representative Compound

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 6, Step C, replacing4-methyl-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine with3-isopropyl-1-phenyl-1H-pyrazol-5-amine (Oakwood, 26 mg, 0.13 mmol),replacing DIEA with Et₃N, and replacing DMF with DCM. The reactionmixture was purified by silica column chromatography, eluting with 0-3%MeOH in DCM, to afford the title compound as a white solid (4 mg, 10%yield). MS (apci) m/z=481.2 (M+H).

Example 9 Representative Compound

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-phenyl-3-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)ureaStep A: Preparation of 5,5,5-trifluoro-3-oxopentanenitrile

To a stirred solution of 2-cyanoacetic acid (1.16 g, 13.7 mmol) and2,2′-bipyridyl (5 mg) in THF (80 mL) cooled to −78° C. was added n-BuLi(2.5 M in hexanes, 10.9 mL, 27.3 mmol) dropwise until a pink colorpersisted. The temperature was raised to −10° C., then the remainder ofthe n-BuLi was added dropwise to maintain the pink color. The reactionmixture was cooled to −78° C., 3,3,3-trifluoropropanolyl chloride (1.00g, 6.83 mmol) was added, and the reaction was stirred at −78° C. for 3hours, and then quenched by the addition of water. The mixture waspartitioned between Et₂O and 1 N HCl. The aqueous layer was extractedwith Et₂O. The combined organic layers were washed with brine, dried andconcentrated. The crude product was purified by silica columnchromatography, eluting with 15% EtOAc in hexanes, to afford the titlecompound (0.790 g, 77%). ¹H NMR (CDCl₃) δ 3.63 (s, 2H), 3.46 (q, 2H).

Step B: Preparation of1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-phenyl-3-(2,2,2-trifluoroethyl)-1H-pyrazol-5-Aurea

Prepared according to the procedure of Example 6, Steps B-C, replacing4,4,4-trifluoro-2-methyl-3-oxobutanenitrile with5,5,5-trifluoro-3-oxopentanenitrile (0.400 g, 2.64 mmol) in Step B andreplacing DIEA with Et₃N, and replacing DMF with DCM in Step C. Thereaction mixture was purified by reverse-phase column chromatography,eluting with 0-80% acetonitrile/water, to afford the title compound as awhite solid (18 mg, 26% yield). MS (apci) m/z=521.2 (M+H).

Example 10 Representative Compound

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 9, replacingphenylhydrazine hydrochloride with (4-fluorophenyl)hydrazinehydrochloride (0.450 g, 2.77 mmol) in Step B. The reaction mixture waspurified by reverse-phase column chromatography, eluting with 0-80%acetonitrile/water, to afford the title compound as a white solid (4 mg,6% yield). MS (apci) m/z=539.2 (M+H).

Example 11

1-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureaStep A: phenyl (1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamate

To a solution of 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (200mg, 0.880 mmol) in EtOAc (8 mL) was added aqueous NaOH (2M, 0.88 mL,1.76 mmol) followed by addition of phenylchloroformate (0.13 mL, 1.06mmol). The reaction mixture was stirred at ambient temperature for 18hours, then additional phenylchloroformate (0.04 mL, 0.32 mmol) wasadded and the reaction mixture was stirred at ambient temperature for 2hours. The reaction mixture was transferred to a separatory funnel with10 mL EtOAc, the phases were separated, and the organic phase was washedwith water and brine, dried (MgSO₄), filtered and concentrated. Thecrude solid was purified by silica column chromatography eluting with0-40% EtOAc/hexane, to afford the title compound (221 mg, 72% yield) asa yellow solid. MS (apci) m/z=348.1 (M+H).

Step B:1-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Phenyl (1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamate (40 mg,0.12 mmol) and3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate A, 32 mg, 0.12 mmol) were diluted with i-PrOH (1 mL). Thesuspension was heated to 50° C. for 42 hours and then heated to 80° C.for 2 hours. The reaction mixture was purified by reverse-phase columnchromatography, eluting with 5-95% acetonitrile/water, and then purifiedby silica column chromatography eluting with 0-95% EtOAc/hexane, toafford the title compound as a white solid (2.2 mg, 4% yield). MS (apci)m/z=535.2 (M+H).

Example 12

1-(3-(2-hydroxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureaStep A:1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 11, Step B, replacing3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine with3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate B). The reaction mixture was partially concentrated, thenpurified by silica column chromatography eluting with 0-50%EtOAc/hexane, to afford the title compound as a white solid (4.2 mg, 6%yield). MS (apci) m/z=601.2 (M+H).

Step B:1-(3-(2-hydroxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

To a solution of1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(4.2 mg, 0.007 mmol) in EtOH (1.5 mL) was added HCl (5-6 M in i-PrOH,0.005 mL). The reaction mixture was stirred at ambient temperature for 1hour and then concentrated. The crude solid was diluted with Et₂O (2×1mL) and concentrated after each addition to give the title compound as awhite solid (3.6 mg, 106% yield). MS (apci) m/z=487.2 (M+H).

1. A compound of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein: X is O, S, NH or N—CN; Ring A is

R¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-3C)alkyl; R² is (1-3C)alkyl[optionally substituted with 1 to 5 fluoros] or (3-4C)cycloalkyl[optionally substituted with one or two fluoros]; R⁶ is H or CH₃; Ring Cis formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²; Ar² is phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl;hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and 0; hetAr² is a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and halogen; R⁴ is hetAr⁴, hetAr⁵ or hydroxy(1-6C)alkoxy;hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and substituted with one or moresubstituents independently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino,trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino; hetAr⁵ is agroup selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more substituents independently selectedfrom F and (1-3C)alkyl optionally substituted with 1-3 fluoros; R⁵ is(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl and (1-6C)alkoxy); or R⁴ and R⁵ together with theatoms to which they are attached form a 5-6 membered saturated,partially unsaturated or unsaturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, or R⁴ and R⁵ together with the atoms to which they areattached form 5-6 membered saturated, partially unsaturated orunsaturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said heterocyclic ring is optionally substituted withone or two substituents independently selected from (1-6C alkyl)C(═O)O—,(1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionallyoxidized to S(═O) or SO₂; R^(3a) is hydrogen, halogen, (1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substitutedwith one or more substituents independently selected from halogen and(1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and halogen; R^(4a) is hydrogen, (1-6C)alkyl,trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl, halogen, CN, CF₃,CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, S and O and optionallysubstituted with 1-2 substituents independently selected from(1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,(3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and R^(5a)is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen.
 2. Acompound according to claim 1, wherein X is O.
 3. (canceled)
 4. Acompound according to claim 1, wherein R¹ is phenyl.
 5. (canceled)
 6. Acompound according to claim 1, wherein R² is (3-4C)cycloalkyl optionallysubstituted with one or two fluoros.
 7. A compound according to claim 1,wherein Ring C is C-1.
 8. A compound according to claim 7, wherein R⁴ ishetAr⁴ or hetAr⁵; and R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl,difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl,pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl,(1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylthio,(3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(1-3C alkyl)amido, orphenyl (optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy). 9.The compound according to claim 8, wherein R⁴ is hetAr⁴.
 10. Thecompound according to claim 9, wherein R⁴ is pyrazole optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl.
 11. The compound according to claim 8, wherein R⁴ is Ar⁵.12. A compound according to claim 7, wherein R⁴ is hydroxyl(1-6C)alkoxy;and R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl and (1-6C)alkoxy).
 13. The compound according toclaim 1, wherein R⁵ is (1-6C)alkyl. 14-15. (canceled)
 16. A compoundaccording to claim 1, wherein R³ is Ar².
 17. A compound according toclaim 16, wherein R³ is phenyl.
 18. A compound according to claim 1,selected from Examples 4, 5, 6, 11 or 12, or a pharmaceuticallyacceptable salt thereof.
 19. A pharmaceutical composition, whichcomprises a compound of Formula I as defined in claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.
 20. A method for treating a disease ordisorder selected from pain, cancer, inflammation, neurodegenerativedisease, Trypanosoma cruzi infection, Sjogren's syndrome, endometriosis,diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome in amammal, which comprises administering to said mammal a therapeuticallyeffective amount of a compound of Formula I as defined in claim 1, or apharmaceutically acceptable salt thereof.
 21. The method of claim 18,wherein the method is a method for treating pain.
 22. The method ofclaim 20, wherein said cancer is a cancer having a dysregulation ofTrkA.
 23. The method of claim 22, wherein the cancer is selected fromnon-small cell lung cancer, papillary thyroid carcinoma, glioblastomamultiforme, acute myeloid leukemia, acute myeloid leukemia, colorectalcarcinoma, large cell neuroendocrine carcinoma, prostate cancer,neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamouscell carcinoma and gastric carcinoma. 24-25. (canceled)
 26. A processfor the preparation of a compound of claim 1, which comprises: (a) for acompound of Formula I where X is O, coupling a corresponding compoundhaving the formula II

 with a corresponding compound having the formula III

 in the presence carbonyldiimidazole or triphosgene and a base; or (b)for a compound of Formula I where X is S, coupling a correspondingcompound having the formula II

 with a corresponding compound of formula III

 in the presence di(1H-imidazol-2-yl)methanethione and a base; or (c)for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

 with a corresponding compound having the formula IV

 where L¹ is a leaving group, in the presence of a base; or (d) for acompound of Formula I where X is O, coupling a corresponding compoundhaving the formula V

 where L² is a leaving group, with a corresponding compound having theformula III

 in the presence of a base; or (e) for a compound of Formula I where Xis O, activating a corresponding compound having the formula VI

 with diphenylphosphoryl azide followed by coupling the activatedintermediate with a corresponding compound having the formula III

 in the presence a base; or (f) for a compound of Formula I where X isO, coupling a corresponding compound having the formula II

 with a corresponding compound having the formula VII

 in the presence of a base; (g) for a compound of Formula I where X isO, coupling a corresponding compound having the formula VIII

 with a corresponding compound having the formula III

 in the presence of a base; and optionally removing protecting groupsand optionally preparing a pharmaceutically acceptable salt thereof.